Methods and compounds for inhibiting beta-amyloid peptide release and/or its synthesis

ABSTRACT

Disclosed are compounds which inhibit β-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer&#39;s disease. Also disclosed pharmaceutical compositions comprising a compound which inhibits β-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer&#39;s disease both prophylactically and therapeutically with such pharmaceutical compositions.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to methods which inhibit cellularβ-amyloid peptide release and/or its synthesis, and, accordingly, haveutility in treating Alzheimer's disease. This invention also relates topharmaceutical compositions comprising such compounds as well as methodsfor inhibiting release of β-amyloid peptide.

REFERENCES

[0003] The following publications, patents and patent applications arecited in this application as superscript numbers:

[0004] 1 l Glenner, et al., “Alzheimer's Disease: Initial Report of thePurification and Characterization of a Novel Cerebrovascular AmyloidProtein”, Biochem. Biophys. Res. Commun., 120:885-890 (1984).

[0005] 2 Glenner, et al., “Polypeptide Marker for Alzheimer's Diseaseand its Use for Diagnosis”, U.S. Pat. No. 4,666,829 issued May 19,1987.

[0006] 3 Selkoe, “The Molecular Pathology of Alzheimer's Disease”,Neuron, 6:487-498 (1991).

[0007] 4 Goate, et al., “Segregation of a Missense Mutation in theAmyloid Precursor Protein Gene with Familial Alzheimer's Disease”,Nature, 349:704-706 (1990).

[0008] 5 Chartier-Harlan, et al., “Early-Onset Alzheimer's DiseaseCaused by Mutations at Codon 717 of the β-Amyloid Precursor ProteingGene”, Nature, 353:844-846 (1989).

[0009] 6 Murrell, et al., “A Mutation in the Amyloid Precursor ProteinAssociated with Hereditary Alzheimer's Disease”, Science, 254:97-99(1991).

[0010] 7 Mullan, et al., “A Pathogenic Mutation for Probable Alzheimer'sDisease in the APP Gene at the N-Terminus of β-Amyloid, Nature Genet.,1:345-347 (1992). 8 Schenk, et al., “Methods and Compositions for theDetection of Soluble β-Amyloid Peptide”, International PatentApplication Publication No. WO 94/10569, published 11 May 1994.

[0011] 9 Selkoe, “Amyloid Protein and Alzheimer's Disease”, ScientificAmerican, pp. 2-8, November, 1991.

[0012] 10 Losse, et al., Tetrahedron, 27:1423-1434 (1971).

[0013] 11 Citron, et al., “Mutation of the β-Amyloid Precursor Proteinin Familial Alzheimer's Disease Increases i-Protein Production, Nature,360:672-674 (1992).

[0014] 12 Hansen, et al.,- “Reexamination andFurther Development of aPrecise and Rapid Dye Method for Measuring Cell Growth/Cell Kill”, J.Immun. Meth., 119:203-210 (1989).

[0015] 13 P. Seubert, Nature (1992) 359:325-327.

[0016] 14 Johnson-Wood et al., PNAS USA (1997) 94:1550-1555.

[0017] 15 Tetrahedron Letters, 34(48), 7685 (1993))

[0018] All of the above publications, patents and patent applicationsare herein incorporated by reference in their entirety to the sameextent as if each individual publication, patent or patent applicationwas specifically and individually indicated to be incorporated byreference in its entirety.

[0019] State of the Art

[0020] Alzheimer's Disease (AD) is a degenerative brain disordercharacterized clinically by progressive loss of memory, cognition,reasoning, judgment and emotional stability that gradually leads toprofound mental deterioration and ultimately death. AD is a very commoncause of progressive mental failure (dementia) in aged humans and isbelieved to represent the fourth most common medical cause of death inthe United States. AD has been observed in races and ethnic groupsworldwide and presents a major present and future public health problem.The disease is currently estimated to affect about two to three millionindividuals in the United States alone. AD is at present incurable. Notreatment that effectively prevents AD or reverses its symptoms andcourse is currently known.

[0021] The brains of individuals with AD exhibit characteristic lesionstermed senile (or amyloid) plaques, amyloid angiopathy (amyloid depositsin blood vessels) and neurofibrillary tangles. Large numbers of theselesions, particularly amyloid plaques and neurofibrillary tangles, aregenerally found in several areas of the human brain important for memoryand cognitive function in patients with AD. Smaller numbers of theselesions in a more restrictive anatomical distribution are also found inthe brains of most aged humans who do not have clinical AD. Amyloidplaques and amyloid angiopathy also characterize the brains ofindividuals with Trisomy 21 (Down's Syndrome) and Hereditary CerebralHemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, adefinitive diagnosis of AD usually requires observing the aforementionedlesions in the brain tissue of patients who have died with the diseaseor, rarely, in small biopsied samples of brain tissue taken during aninvasive neurosurgical procedure.

[0022] The principal chemical constituent of the amyloid plaques andvascular amyloid deposits (amyloid angiopathy) characteristic of AD andthe other disorders mentioned above is an approximately 4.2 kilodalton(kD) protein of about 39-43 amino acids designated the β-amyloid peptide(SAP) or sometimes Aβ, AβP or β/A4. β-Amyloid peptide was first purifiedand a partial amino acid sequence was provided by Glenner, et al.¹ Theisolation procedure and the sequence data for the first 28 amino acidsare described in U.S. Pat. No. 4,666,829².

[0023] Molecular biological and protein chemical analyses have shownthat the β-amyloid peptide is a small fragment of a much largerprecursor protein (APP), that is normally produced by cells in manytissues of various animals, including humans. Knowledge of the structureof the gene encoding the APP has demonstrated that #-amyloid peptidearises as a peptide fragment that is cleaved from APP by proteaseenzyme(s). The precise biochemical mechanism by which the β-amyloidpeptide fragment is cleaved from APP and subsequently deposited asamyloid plaques in the cerebral tissue and in the walls of the cerebraland meningeal blood vessels is currently unknown.

[0024] Several lines of evidence indicate that progressive cerebraldeposition of β-amyloid peptide plays a seminal role in the pathogenesisof AD and can precede cognitive symptoms by years or decades. See, forexample, Selkoe³. The most important line of evidence is the discoverythat missense DNA mutations at amino acid 717 of the 770-amino acidisoform of APP can be found in affected members but not unaffectedmembers of several families with a genetically determined (familial)form of AD (Goate, et al.⁴; Chartier-Harlan, et al.⁵; and Murrell, etal.⁶) and is referred to as the Swedish variant. A double mutationchanging lysine⁵⁹⁵-methionine⁵⁹⁶ to asparagine⁵⁹⁵-leucine⁵⁹⁶ (withreference to the 695 isoform) found in a Swedish family was reported in1992 (Mullan, et al.⁷). Genetic linkage analyses have demonstrated thatthese mutations, as well as certain other mutations in the APP gene, arethe specific molecular cause of AD in the affected members of suchfamilies. In addition, a mutation at amino acid 693 of the 770-aminoacid isoform of APP has been identified as the cause of the β-amyloidpeptide deposition disease, HCHWA-D, and a change from alanine toglycine at amino acid 692 appears to cause a phenotype that resembles ADis some patients but HCHWA-D in others. The discovery of these and othermutations in APP in genetically based cases of AD prove that alterationof APP and subsequent deposition of its β-amyloid peptide fragment cancause AD.

[0025] Despite the progress which has been made in understanding theunderlying mechanisms of AD and other β-amyloid peptide relateddiseases, there remains a need to develop methods and compositions fortreatment of the disease(s). Ideally, the treatment methods wouldadvantageously be based on drugs which are capable of inhibiting,-amyloid peptide release and/or its synthesis in vivo.

SUMMARY OF THE INVEON

[0026] This invention is directed to the discovery of a class ofcompounds which inhibit β-amyloid peptide release and/or its synthesisand, therefore, are useful in the prevention of AD in patientssusceptable to AD and/or in the treatment of patients with AD in orderto inhibit further deterioration in their condition. The class ofcompounds having the described properties are defined by formula Ibelow:

[0027] wherein

[0028] R¹ is selected from the group consisting of alky, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;

[0029] R² is selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;

[0030] each R³ is independently selected from the group consisting ofhydrogen and methyl and R³ together with R⁴ can be fused to form acyclic structure of from 3 to 8 atoms which is optionally fused with anaryl or heteroaryl group;

[0031] each R⁴ is independently selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl,heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl andsubstituted alkynyl;

[0032] each R⁵ is selected from hydrogen and methyl or together with R⁴forms a cycloalkyl group of from 3 to 6 carbon atoms;

[0033] X is selected from the group consisting of —C(O)Y and —C(S)Ywhere Y is selected from the group consisting of

[0034] (a) alkyl or cycloalkyl,

[0035] (b) substituted alkyl with the proviso that the substitution onsaid substituted alkyl do not include α-haloalkyl, α-diazoalkyl,α-OC(O)alkyl, or α-OC(O)aryl groups,

[0036] (c) alkoxy or thioalkoxy,

[0037] (d) substituted alkoxy or substituted thioalkoxy,

[0038] (e) hydroxy,

[0039] (f) aryl,

[0040] (g) heteroaryl,

[0041] (h) heterocyclic,

[0042] (i) —NR′R″ where R′ and R″ are independently selected fromhydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substitutedalkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclic, where one of R′ or R′ is hydroxy or alkoxy, and where R′and R″ are joined to form a cyclic group having from 2 to 8 carbon atomsoptionally containing 1 to 2 additional heteroatoms selected fromoxygen, sulfur and nitrogen and optionally substituted with one or morealkyl, alkoxy or carboxylalkyl groups,

[0043] (i) —NHSO₂-R⁸ where R⁸ is selected from alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic,

[0044] (k) —NR⁹NR¹⁰R¹⁰ where R⁹ is hydrogen or alkyl, and each R¹⁰ isindependently selected from hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and

[0045] (l) —ONR⁹[C(O)O]_(z)R¹⁰ where z is zero or one, R⁹ and R¹⁰ are asdefined above;

[0046] X can also be —CR⁶R⁶Y′ where each R⁶ is independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl and heterocyclic and Y′ is selected fromthe group consisting of hydroxyl, amino, thiol, alkoxy, substitutedalkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R⁷, —SSR⁷, —SSC(O)R⁷where R⁷ is selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,

[0047] X′ is hydrogen, hydroxy, or fluoro;

[0048] X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form anoxo group,

[0049] Z is selected from the group consisting of a bond covalentlylinking R¹ to —CX′X″—, oxygen and sulfur;

[0050] n is an integer equal to 1 or 2; and

[0051] pharmaceutically acceptable salts thereof with the provisos that:

[0052] A. when R¹ is phenyl or 3-nitrophenyl, R² is methyl, R³ ishydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OH;

[0053] B. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁴ is—CH(OH)CH₃ derived from D-threonine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH₃;

[0054] C. when R¹ is phenyl, R² is methyl, R⁴ is benzyl, R⁵ is hydrogen,X is methoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1,then R³ is not methyl;

[0055] D. when R¹ is iso-propyl, R² is —CH₂C(O)NH₂, R³ is hydrogen, R⁴is iso-butyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and nis 1, then X is not —C(O)OCH₃;

[0056] E. when R¹ is phenyl, R² is methyl, R⁵ is hydrogen, X is—C(O)OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R³, thenitrogen atom attached to R³, and R⁴ do not form1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl;

[0057] F. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁵ ishydrogen, X is —C(O)OCH₃, X′ and X′ are hydrogen, Z is a bond, and n is1, then R⁴ is not 4-amino-n-butyl;

[0058] G. when R¹ is 3-nitrophenyl, R² is methyl, R³ is hydrogen, R⁴ is—CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and nis 1, then X is not —C(O)NH₂ or —CH₂OH;

[0059] H. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁵ ishydrogen, X is —CH₂OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is1, then R⁴ is not benzyl or ethyl;

[0060] I. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is methyl, R⁴is methyl, R⁵ is hydrogen, X′ and X′ are hydrogen, Z is a bond, and n is1, then X is not —CHOHO;

[0061] J. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —CHOHφ or —CH₂OH;

[0062] K. when R₁ is N-(2-pyrrolidinonyl), R₂ is methyl, R₃ is hydrogen,R₄ is benzyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and nis 1, then X is not —C(O)OCH₃;

[0063] L. when R¹ is 3,5-difluorophenyl, R² is methyl derived fromD-alanine, R³ is hydrogen, R⁴ is phenyl derived from D-phenylglycine, R⁵is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X isnot —C(O)NH-benzyl;

[0064] M. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen,R⁴ is hydrogen, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, andn is 1, then X is not —CH₂OH;

[0065] N. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen,R⁴ is 4-phenylphenyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is abond, and n is 1, then X is not —C(O)NHC(CH)₃; and

[0066] O. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)NHCH(CH₃)φ.

[0067] Preferably, the compounds of this invention are derived fromL-amino acids and, accordingly, are represented by formula IA:

[0068] Accordingly, in one of its method aspects, this invention isdirected to a method for inhibiting -amyloid peptide release and/or itssynthesis in a cell which method comprises administering to such a cellan amount of a compound or a mixture of compounds of formula I aboveeffective in inhibiting the cellular release and/or synthesis ofβ-amyloid peptide.

[0069] Because the in vivo generation of β-amyloid peptide is associatedwith the pathogenesis of AD^(8.9), the compounds of formula I can alsobe employed in conjunction with a pharmaceutical composition toprophylactically and/or therapeutically prevent and/or treat AD.Accordingly, in another of its method aspects, this invention isdirected to a prophylactic method for preventing the onset of AD in apatient at risk for developing AD which method comprises administeringto said patient a pharmaceutical composition comprising apharmaceutically inert carrier and an effective amount of a compound ora mixture of compounds of formula I above.

[0070] In yet another of its method aspects, this invention is directedto a therapeutic method for treating a patient with AD in order toinhibit further deterioration in the condition of that patient whichmethod comprises administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically inert carrier and an effectiveamount of a compound or a mixture of compounds of formula I above.

[0071] Compounds suitable for use in the claimed methods include, by wayof example only, the following:

[0072] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatemethyl ester

[0073] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methylester

[0074]N-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0075]N-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0076]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0077]N-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0078]N-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0079]N-(3-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0080]N-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0081] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatetert-butyl ester

[0082] N-[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester

[0083] N-[N-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl ester

[0084]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)propoxy]phenylalaninemethyl ester

[0085]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalaninemethyl ester

[0086] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methylester

[0087]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(carboxymethoxy)phenylalaninemethyl ester

[0088]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(2-morpholinoethoxy)phenylalaninemethyl ester

[0089]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylamino)hexanoatemethyl ester

[0090]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionatemethyl ester

[0091]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionatemethyl ester

[0092] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-proline methylester

[0093]1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylatemethyl ester

[0094]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-anino-3-(4-pyridyl)propionatemethyl ester

[0095]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionatemethyl ester

[0096]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionatemethyl ester

[0097]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(2-morpholinoethoxy)phenylalaninamide

[0098]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionamide

[0099] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester

[0100]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4-pyridyl)propionamide

[0101]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(2-pyridyl)propionamide

[0102]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol4-yl)propionatemethyl ester

[0103] 2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl ester

[0104]N-(3-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0105] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(1-naphthyl)propionate methyl ester

[0106]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propionatemethyl ester

[0107]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propionatemethyl ester

[0108] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninebenzyl ester

[0109] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine3-bromopropyl ester

[0110] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine3-iodopropyl ester

[0111] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butylester

[0112]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamide

[0113]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamide

[0114]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N_(ε)-(tert-butoxycarbonyl)-L-lysine methyl ester

[0115] methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoateN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl ester

[0116] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropylester

[0117]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetamide

[0118] N-[N-(phenylacetyl)-L-alaninyl]-L-threonine methyl ester

[0119] N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

[0120] N′-[N-(phenylacetyl)-L-alaninyl]-L-alariinamide

[0121] N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0122] N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamide

[0123]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetateethyl ester

[0124] N-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

[0125] N,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0126] N,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

[0127] N,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-vafinamide

[0128] N-methyl-N′-[N-phenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0129] N-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-vainamide

[0130]N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0131]N,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0132] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[0133]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetatemethyl ester

[0134] 40N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acetatemethyl ester

[0135]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetateethyl ester

[0136]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetateethyl ester

[0137] N-[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0138] N-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0139] N-[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methylester

[0140] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxylate methyl ester

[0141]N-2-(N,N-dimethylamino)ethyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0142] N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0143] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester

[0144] N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester

[0145] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-phenylalanine methylester

[0146] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl ester

[0147] N-[N-(3-nitrophenylacetyl)-L-alaninyl]glycine ethyl ester

[0148]N-hydroxy-N′-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamide

[0149] N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl ester

[0150]N-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propionatemethyl ester

[0151] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine ethyl ester

[0152] N-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl ester

[0153] N-[N-[N-(isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanineiso-butyl ester

[0154] N-[N-(isovaleryl)-L-phenylalaninyl]-L-alanine iso-butyl ester

[0155] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester

[0156] 1-[N-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2-carboxylateethyl ester

[0157] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0158]N-methoxy-N-methyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide

[0159]N-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0160]N,N-di-n-propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0161] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide

[0162]N-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0163]N′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamide

[0164] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninemethyl ester

[0165] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0166] N-iso-butyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide

[0167]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0168]N-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0169]N-(4-nitrophenyl)-N′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamide

[0170]N-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0171]N-benzyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0172]N-(3,5-difluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0173]N-(3-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0174]N-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0175]N-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0176] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methylester

[0177]N-(4-methoxybenzyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0178] N-[N-(phenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester

[0179]N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycinemethyl ester

[0180] N-[N-(cyclohexylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester

[0181] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinemethyl ester

[0182]N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-phenylglycinemethyl ester

[0183]N-(2-phenylethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0184] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide

[0185]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionatemethyl ester

[0186] N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide

[0187] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl ester

[0188]N-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0189]N-[(S)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0190]N-(4-fluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0191]N-(4-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0192]N-(4-trifluoromethylbenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0193]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionateethyl ester

[0194] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninetert-butyl ester

[0195]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionatemethyl ester

[0196]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetateethyl ester

[0197]N-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0198] N-[N-(isovaleryl)-2-amino-2-cyclohexylacetyl]-L-alanine ethylester

[0199]N-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0200]N-(2-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0201] N-[N-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0202] N-[N-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0203] N-[N-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0204]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)acetateethyl ester

[0205]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)acetateethyl ester

[0206] N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethylester

[0207]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionateethyl ester

[0208] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycineneopentyl ester

[0209]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0210] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinetert-butyl ester

[0211] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0212] 4-[N-[N-(³-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine

[0213] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester

[0214] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl ester

[0215] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoatemethyl ester

[0216]4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl]morpholine

[0217]4-[N-[N-(³-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine

[0218] N-[N-(³-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester

[0219] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine

[0220] N-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valineethyl

[0221] V-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoatemethyl ester

[0222] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methyl ester

[0223] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methylester

[0224]N-2-methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0225]N-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0226]N-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0227]N-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0228]N-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0229]N-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0230]3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine

[0231] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoatemethyl ester

[0232] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoatemethyl ester

[0233]N-(R)-sec-butyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0234]1[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine

[0235]N-(S)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0236] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester

[0237]N-2-fluoroethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0238]N-[(S)-6-methyl-3-oxohept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0239]N-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramide

[0240]N-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamide

[0241]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetatemethyl ester

[0242]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamide

[0243]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetatemethyl ester

[0244]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetateethyl ester

[0245]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)acetatemethyl ester

[0246]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetatemethyl ester

[0247]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetateethyl ester

[0248]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetatemethyl ester

[0249]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetatetert-butyl ester

[0250]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticacid

[0251]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)acetatemethyl ester

[0252]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetatemethyl ester

[0253]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetatemethyl ester

[0254]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetatemethyl ester

[0255]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetatemethyl ester

[0256]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl)acetatemethyl ester

[0257](3S,4S)-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-4-amino-3-hydroxy-5-phenylpentanoatemethyl ester

[0258]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-arninohex-4-enoatemethyl ester

[0259] N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylglycine tert-butylester

[0260]N-tert-butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(4-phenylphenyl)acetamide

[0261]N-[N-(3,5-difuorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycinetert-Butyl Ester

[0262] N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinetert-butyl ester

[0263] N-[N-(3,⁵-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinemethyl ester

[0264] N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methylester

[0265] N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinemethyl ester

[0266] N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycinemethyl ester

[0267] N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycinemethyl ester

[0268] N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycine methylester

[0269] N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinemethyl ester

[0270] N-[N-(phenylacetyl)-L-alaninyl]-L-alanine methyl ester

[0271] N-[N-(phenylacetyl)-L-alaninyl]-Lleucine methyl ester

[0272] N-[N-(phenylacetyl)-L-alaninyl]-L-isoleucine methyl ester

[0273] N-[N-(phenylacetyl)-L-alaninyl]-L-proline methyl ester

[0274] N-[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester

[0275] N-[N-(phenylacetyl)-L-alaninyl]-N-(tert-butoxycarbonyl)-L-lysinemethyl ester

[0276] N-[N-(phenylacetyl)-L-alaninyl]-glycine methyl ester

[0277] N-[N-(phenylacetyl)-L-alaninyl]-L-valine methyl ester

[0278] N-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester

[0279] N-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methylester

[0280] N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine

[0281] N-[N-(phenylacetyl)-L-alaninyl]-L-N-methylalanine methyl ester

[0282] N-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl ester

[0283] N-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl ester

[0284]N-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0285] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-hydroxyprolineethyl ester

[0286] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester

[0287] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide

[0288]1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylatemethyl ester

[0289]N-[(S)-3-hydroxy-6-methylhept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0290] N-[(S)-2-hydroxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L- alaninamide

[0291]N-[N-(3,5-difluorophenyl-α-fluoroacetyl)-L-alaniny]-L-phenylglycinetert-butyl ester

[0292]N-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycinemethyl ester

[0293]N-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0294]N-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0295]N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0296]N-2-methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide

[0297]N-[(S)-α-hydroxy-α-phenyl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0298]N-[(S)-2-hydroxy-1,2-diphenylethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0299]N-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0300]N-[α-hydroxy-α′-(4-hydroxyphenyl)-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0301]N-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[0302]N-[α-hydroxy-α′-pyrid-2-yl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0303]N-[α-hydroxy-α-pyrid-4-yl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0304]N-[(S)-1-hydroxy-4-methylpent-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0305]N-[α-methoxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0306]N-[1-hydroxy-3-methyl-but-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0307]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)acetatemethyl ester

[0308]N-[1-hydroxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0309]N-[(S)-2-methoxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0310]N-[(S)-1-methoxy-2-phenyl-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0311]N-[(S)-1-acetoxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0312]N-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0313]N-[2-hydroxy-1-(thien-2-yl)ethyl3-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0314]N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0315]N-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalaninetert-butyl ester

[0316]N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol

[0317] N-[N-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol

[0318] N-[N-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinol

[0319]N-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide

[0320] N-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide

[0321] N-[N-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamide

[0322] N-[N-(n-caprotyl)-L-alaninyl]-L-phenylglycinamide

[0323] N-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycinemethyl ester

[0324] N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycinemethyl ester

[0325] N-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycinemethyl ester

[0326] N-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycinemethyl ester

[0327]N-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycinemethyl ester

[0328]N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycinemethyl ester

[0329]N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycinemethyl ester

[0330]N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylglycinemethyl ester

[0331]N-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl ester

[0332]N-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl ester

[0333]N-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycinemethyl ester

[0334] N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butylester

[0335] N-[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl ester

[0336] N-[N-(cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl ester

[0337] N-[N-(tert-butylacetyl)-L-alaninyl]-L-phenylglycinamide

[0338]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamide

[0339]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2-yl)glycinamide

[0340]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2-yl)glycinamide

[0341]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)glycinamide

[0342]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide

[0343] N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamide

[0344]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide

[0345]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0346]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0347]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothien-2-yl)glycinamide

[0348]N-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)phenylglycinamide

[0349]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamide

[0350]N-(S)-(−)-α-methylbenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0351]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamide

[0352]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenylglycinamide

[0353]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamide

[0354]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylglycinamide

[0355]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamide

[0356]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)phenylglycinamide

[0357]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphenyl)phenylglycinamide

[0358]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)phenylglycinamide

[0359]N-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamide

[0360]N-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)phenylglycinamide

[0361]N-[N-(3,5-difluorophenyl-c-hydroxyacetyl)-L-alaninyl]-L-phenylglycinetert-butyl ester

[0362]N-tert-butyl-N′-[N-(3,5-difluorophenyl-α,α-difluoroacetyl)-L-alaninyl]-L-phenylglycinamide

[0363] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinetert-butyl ester

[0364]N-[(S)-1-oxo-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0365]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycinetert-butyl ester

[0366][N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine

[0367]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycinemethyl ester

[0368] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-ter-butoxycarbonyl(hydroxyl amine) ester

[0369]N-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0370]N-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0371]N-methoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0372][N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidine

[0373]N-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0374]N-cyclopropanemethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamride

[0375]N-methoxy-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0376]N-2-methylprop-2-enyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0377]N-(pyrid-3-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0378] N-(pyrid-4-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0379]N-furfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0380]N-cyclopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0381]N-1-benzylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0382]N,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0383] N-2,2,6,6-tetramethylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0384]N-2-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0385]N-4-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0386]N-1-ethoxycarbonylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0387]N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0388]N-tert-butoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[0389] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-butyl(hydroxylamine) ester

[0390] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinehydrazide

[0391] N-(1-ethoxyethen-1-yl)-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinehydrazide

[0392] N-[N(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester

[0393]N-4-(phenyl)butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0394]N-3-(4-iodophenoxy)propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0395]N-6-(amino)hexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl3-D,L-phenylglycinamideHydrochloride

[0396]N-1-(phthalimido)pent-2-yl-N′-(3,5-difluorophenylacetyl)-L-alaninamnide

[0397]N-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycinemethyl ester

[0398] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine

[0399] N-[N-(cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine tert-butylester

[0400]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycineiso-propyl ester

[0401] N-(isopropyl)N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0402] N-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine tert-butylester

[0403] N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine tert-butylester

[0404] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycineiso-butyl ester

[0405] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycinemethyl ester

[0406] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-α-phenyl)prolinemethyl ester

[0407] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidine methylester

[0408]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorobenzothiophen-2-yl)acetatemethyl ester

[0409]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionatetert-butyl ester

[0410] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamidetert-butyl ester

[0411]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide

[0412] N-[N-(3,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0413] N-[N-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0414] N-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0415] N-[N-(³-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0416] N-[N-(⁴-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0417] N-[N-(³-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0418] N-[N-(⁴-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0419]N-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0420] N-[N-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0421] N-[N-(²-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0422] N-[N-(I-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide

[0423] N-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide

[0424] N-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0425] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine

[0426] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[0427]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)acetamide

[0428] N′-[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide

[0429] N′-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide

[0430]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfonamide

[0431]N″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide

[0432]N″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[0433]N′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide

[0434]N″-methyl-N″-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide

[0435]N′-4-fluorobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0436]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycineneopentyl ester

[0437]N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinemethyl ester

[0438] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinetert-butyl ester

[0439]N-[N-(3,5-difuorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycinemethyl ester

[0440]N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycinemethyl ester

[0441] N-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycinemethyl ester

[0442] N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methylester

[0443] N″-4-methylphenyl-N′- [N-(3,S-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0444]N″-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0445]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide

[0446] N′-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide

[0447]N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide

[0448]N′-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide

[0449] N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide

[0450]N-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0451]N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0452]N-[1-phenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0453]N-[1-phenyl-2-oxo-pentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0454]N-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide

[0455]N-[1-phenyl-2-oxo-butan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide

[0456]N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide

[0457]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-α-hydroxyphenylalaninemethyl ester

[0458]N″-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0459] N-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide

[0460]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinetert-butyl ester

[0461]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycinetert-butyl ester

[0462] [N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline)methyl ester

[0463]N″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylphenylglycinamide

[0464]N″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylacetenyl)phenylglycinamide

[0465]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioaide

[0466] N-[1,3-diphenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0467]N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0468]N-[1-phenyl-2-oxo-hexan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0469]N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0470]N″-n-hexyl-6-biotinamidyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide

[0471] N′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine

[0472] N′-[N-(²-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycinemethyl ester

[0473] N″-tert-butylN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide

[0474] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycinemethyl ester

[0475]N-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[0476]N′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine

[0477]N′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycinetert-butyl ester

[0478]N′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine

[0479]N′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl-L-2-phenylglycinetert-butyl ester

[0480]N-[2-hydroxy-1-(S)phenyleth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamide

[0481]N-[2-hydroxyeth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[0482]N′-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycinetert-butyl ester

[0483] [N-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methylester

[0484] [N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methylester

[0485] [N-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycinemethyl ester

[0486] [N-(3-aminoproprionyl)-L-alaninyl]-L-phenylglycine tert-butylester

[0487][N-(3-tert-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycinetert-butyl ester

[0488] The pharmaceutical compositions described above comprise apharmaceutically inert carrier and a compound of the formula I above.

[0489] In formula I above, X″ is preferably hydrogen and X′is preferablyhydrogen or fluoro.

[0490] In formula I above, Z is preferably a covalent bond linking R¹ to—CX′X″—.

[0491] In formula I above, preferred R¹ unsubstituted aryl groupsinclude, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.

[0492] Preferred R¹ substituted aryl groups include, for example,monosubstituted phenyls (preferably 3 or 5 substituents); disubstitutedphenyls (preferably 3,5 substituents); and trisubstituted phenyls(preferably 3,4,5 substituents). Preferably, the substituted phenylgroups do not include more than 3 substituents.

[0493] Examples of substituted phenyls include, for instance,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl,4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl,3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2-hydroxy-phenyl, 2-methylphenyl,2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl,2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl,3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,2,4-dichlorophenyl, and 2,5-difluorophenyl.

[0494] Preferred R¹ alkaryl groups include, by way of example, benzyl,2-phenylethyl, 3-phenyl-n-propyl, and the like.

[0495] Preferred R¹ alkyl, substituted alkyl, alkenyl, cycloalkyl andcycloalkenyl groups include, by way of example, iso-propyl, n-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, —CH₂CH═CH₂,—CH₂CH═CH(CH₂)₄CH₃, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclohex-l-enyl, —CH₂—cyclopropyl, —CH₂-cyclobutyl, —CH₂-cyclohexyl,—CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl, —CH₂CH₂-cyclobutyl,—CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl, aminomethyl,N-tert-butoxycarbonylaminomethyl, and the like.

[0496] Preferred R¹ heteroaryls and substituted heteroaryls include, byway of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls(including 5-fluoropyrid-3-yl), chloropyridyls (including5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl,2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl,2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.

[0497] Preferably R² is selected from the group consisting of hydrogen,alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic.Particularly preferred R² substituents include, by way of example,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,phenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-methoxyphenyl, benzyl,cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl,thien-3-yl, —CH₂CH₂SCH₃, —CH₂OCH₂φ, —CH(CH₃)OCH₂0, —CH(OH)CH₃, —CH₂OHand the like. As noted below, R² (as well as R⁴) is preferably the sidechain of an L-amino acid.

[0498] Preferably, R³ is hydrogen, methyl or together with R⁴ and thenitrogen to which R³ is attached forms pyrrolidin-2-yl,2,3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl,1,2,3,4-tetrahydroisoquinolin-3-yl, and the like.

[0499] Preferred R⁴ substituents include, for example, hydrogen, methyl,ethyl, iso-propyl, n-propyl, n-butyl, sec-butyl, iso-butyl, cyclopentyl,cyclohexyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH₂-cyclopropyl,—CH₂-cyclohexyl, —CH₂-indol-3-yl, phenyl, p-(phenyl)phenyl,m-(phenyl)phenyl o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-phenylphenyl, 3,5-difluorophenyl,p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl, 4-(N-morpholino-CH₂CH₂O)-benzyl,—CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl, —CH₂-(3-tetrahydrofuranyl),—CH₂-thien-2-yl, —CH₂-thiazol-4-yl, —CH₂( 1-methyl)cyclopropyl,—CH₂-thien-3-yl, thien-3-yl, thien-2-yl, —CH₂—C(O)O-t-butyl,—CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂, 2-methylcyclopentyl, -cyclohex-2-enyl,—CH[CH(CH₃)₂]COOCH₃, —(CH₂)₂SCH₃, —CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂,—CH₂CH═CHCH₃ (cis and trans), —CH₂OH, —CH(OH)CH₃, —CH(O-t-butyl)CH₃,—CH₂OCH₃, —(CH₂)₄NH-Bec, —(CH)₄NH₂, —(CH₂)₄N(CH₃)₂, —CH₂-pyridyl (e.g.,2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and4-pyridyl), -CH₂-naphthyl (e.g., 1-naphthyl and 2-naphthyl),—CH₂-(N-morpholino), p-(N-morpholino-CH₂CH₂O)-benzyl,benzo[b]thiophen-2-yl, benzoob]thiophen-3-yl,5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl,benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, -CH₂-N-phthalimidyl,2-methylthiazol-4-yl, and thieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl,4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl,4-ethylphenyl, 2-benzylphenyl, (4-ethylphenyl)phenyl,4-tert-butylphenyl, 4-n-butylphenyl, o-(4-chlorophenoxy)phenyl,furan-2-yl, 4-phenylacetylenylphenyl and the like.

[0500] Preferably, R⁵ is hydrogen. However, in another embodiment, R⁴and R⁵ are fused to form a cycloalkyl group including, for example,cyclopropyl, cyclobutyl, and the like.

[0501] One preferred X substituent is —C(O)Y. Preferably Y is hydroxy,alkoxy or substituted alkoxy such as methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy,2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy,—ONHC(O)OC(CH₃), —ONHC(CH₃)₃ and the like. Another preferred Y group is—NR′R″ where R′ and R″ are as defined above. Such preferred Y groupsinclude, by way of example, amino (—NH₂), —NH(iso-butyl),—NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino,N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl,N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl,—NH-methallyl, —NHCH₂-(furan-2-yl), —NHCH₂-cyclopropyl, —NH(tert-butyl),—NH(p-methylphenyl), —NHOCH₃, —NHCH₂(p-fluorophenyl), —NHCH₂CH₂OCH₃,—NH-cyclopentyl, —NH-cyclohexyl, —NHCH₂CH₂N(CH₃)₂, —NHCH₂C(CH₃)₃,—NHCH₂-(pyrid-2-yl), —NHCH₂-(pyrid-3-yl), —NHCH₂-(pyrid-4-yl),N-thiazolindinyl, —N(CH₂CH₂CH₃)₂, —N[CH₂CH(CH₃)₂]₂, —NHOH, —NH(p-NO₂-φ),—NHCH₂(p-NO₂-φ, —NHCH₂(m-NO₂-φ), —N(CH₃)OCH₃, —N(CH₃)CH₂- 0,—NHCH₂-(3,5-di-fluorophenyl), —NHCH₂CH₂F, —NHCH₂(p-CH₃O-φ),—NHCH₂(m—CH₃Oφ), —NHCH₂(p-CF₃-φ), —N(CH₃)CH₂CH₂OCH₃, —NHCH₂CH₂φ,—NHCH(CH₃)φ, —NHCH₂—(p-F-φ), —N(CH₃)CH₂CH₂N(CH₃)₂,—NHCH₂-(tetrahydrofuran-2-yl), —NHCH₂(p-trifluoromethylphenyl),—NHCH₂C(CH₃)═CH₂, —NH—[(p-benzyl)pyrid-4-yl],-NH-1(2,6-dimethyl)pyrid-4-yl], —NH—(2-methylcyclohexyl),—NH—(4-methylcyclohexyl), —NH-[N-ethoxycarbonyl]-piperidin-4-yl,—NHOC(CH₃)₃, —NHCH₂CH₂CH₂CH₂-φ, —C(O)NH(CH₂)₃O-(p-CH₃)φ,—C(O)NH(CH₂)₆NH₂, —NH-(tetrahydrofuran-2-yl), —N(CH₃)φ,—NH(CH)₄NHC(O)-(2-hydroxy-4-azido)-phenyl, —NH(CH₂)₆-(biotinamidyl), andthe like.

[0502] Another preferred Y group is an alkyl group such as methyl,ethyl, iso-propyl, n-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl,—CH₂CH₂CH(CH₃)₂, —CH₂-pyridy-2-yl, —CH₂-pyridy-3-yl,—CH₂-pyridy-4-yl,—CH₂-fur-2-yl, and the like; a substituted alkyl group such as benzyl; acycloalkyl group such as cyclopentyl; and an aryl group such as phenyl.

[0503] Still another preferred Y group is —NHSO₂—R where R is selectedfrom alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,aryl, heteroaryl and heterocyclic. Such groups are exemplified byNH—SO₂—CH₃.

[0504] Preferred Y′ groups include a substituted alkyl group such as—CH₂OH, —CH(OH)CH₂CH₂CH(CH₃)₂, —CH(OH)φ, —CH(OH)CH₂C(O)OCH₃, —C (OH)(CH₃)₂, —CH₂OCH₃, —CH₂OC(O)OCH₃, —CH₂0C(O)C(CH₃)₃, and the like.

[0505] Preferred compounds for use in the methods of this inventioninclude those set forth in the tables below:

R¹ R² R³ R⁴ R⁵ X t-butyl —CH₃ H -φ H —C(O)NH₂ thien-2-yl —CH₃ H -φ H—C(O)NH₂ n-butyl —CH₃ H -φ H —C(O)NH₂ cyclopentyl —CH₃ H -φ H—C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₂CH₃ H —C(O)OCH₃ 3,5-di-F-φ-—CH₃ H —CH₂-imidazol-4-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₂CH₃ H—C(O)NHCH₂-φ 3,5-di-F-φ- —CH₃ H —(CH₂)₃CH₃ H —C(O)NHCH₂CH₂N(CH₃)₂3,5-di-F-φ- —CH₃ H —(CH₂)₃CH₃ H —C(O)NHCH₂CH₂OCH₃ 3,5-di-F-φ- —CH₃ H—CH₂-φ H —C(O)NHCH₃CH₂N(CH₃)₂ 3,5-di-F-φ- —CH₃ H —CH₂-φ H—C(O)NHCH₂-(pyrid-4-yl) 3,5-di-F-φ- —CH₃ H —CH₂-φ H—C(O)NHCH₂-(pyrid-3-yl) 3,5-di-F-φ- —CH₃ H —(CH₂)₃CH₃ H—C(O)NHCH₂-pyrid-4-yl 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₂CH₃ H —C(O)OC(CH₃)₃CH₂═CHCH₂— —CH₃ H —CH₂φ H —C(O)OCH₃ CH₃(CH₂)₄CH═CHCH₂— —CH₃ H —CH₂φ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H p-(CH₃)₂NCH₂CH₂CH₂O— H —C(O)OCH₃ benzyl-3,5-di-F-φ- —CH₃ H p-(CH₃)₃COC(O)CH₂O— H —C(O)OCH₃ benzyl- 3,5-di-F-φ-—CH₃ H p-hydroxybenzyl- H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H p-HOOCCH₂O-benzylH —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H p-(N-morpholino- H —C(O)OCH₃CH₂CH₂O-benzyl- 3,5-di-F-φ- —CH₃ H —(CH₂)₄—N(CH₃)₂ H —C(O)OCH₃3,5-di-F-φ- —CH₃ H —CH₂-(pyrid-2-yl) H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H—CH₂—(pyrid-3-yl) H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ R₃/R₄ and N = H —C(O)OCH₃L-pyrrolidinyl φ- —CH₃ R₃/R₄ and N = H —C(O)OCH₃ piperidin-2-yl3,5-di-F-φ- —CH₃ H —CH₂-(pyrid-4-yl) H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H—CH₂OCH₃ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-(N-morpholino) H —C(O)OCH₃3,5-di-F-φ- —CH₃ H p-(N-morpholino- H —C(O)NHCH₂CH₂OCH₃CH₂CH₂—O)-benzyl- 3,5-di-F-φ- —CH₃ H —CH₂OCH₃ H —C(O)NHCH₂CH₂OCH₃3,5-di-F-φ- —CH₃ H H H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-pyrid-4-yl H—C(O)NHCH₂CH₂OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-pyrid-2-yl H —C(O)NHCH₂CH₂OCH₃3,5-di-F-φ- —CH₃ H —CH₂-thiazol-4-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ R₃/R₄and N = H —C(O)OCH₃ 1,2,3,4-tetrahydro- isoquinolin-3-yl 3,5-di-F-φ-—CH₃ H —CH₂-φ H —C(O)NHCH₂-(m-CH₃O-φ) 3,5-di-F-φ- —CH₃ H —CH₂-1-naphthylH —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-2-naphthyl H —C(O)OCH₃ 3,5-di-F-φ-—CH₃ H —CH₂-thien-2-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-φ H—C(O)OCH₂CH₂CH₂CH₂Br 3,5-di-F-φ- —CH₃ H —CH₂-φ H —C(O)OCH₂CH₂CH₂I3,5-di-F-φ- —CH₃ H —CH₂CH(CH₃)₂ H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ Hpyrid-2-yl H —C(O)NH₂ 3,5-di-F-φ- —CH₃ H pyrid-3-yl H —C(O)NH₂3,5-di-F-φ- —CH₃ H —(CH₂)₄—NHC(O)OC(CH₃)₃ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H—CH₂CH₂-φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H H H —C(O)OCH₂CH₂φ 3,5-di-F-φ-—CH₃ H H H —C(O)OCH₂CH₂CH₂φ 3,5-di-F-φ- —CH₃ H pyrid-4-yl H —C(O)NH₂ φ-—CH₃ H —CH(OH)CH₃ H —C(O)OCH₃ φ- —CH₃ H —CH₂CH(CH₃)₂ H —C(O)NH₂ φ- —CH₃H —CH₃ H —C(O)NH₃ φ- —CH₃ H —CH₂-φ H —C(O)NH₂ φ- —CH₃ H —CH(CH₃₎ ₂ H—C(O)NH₂ 3,5-di-F-φ- —CH₃ H pyrid-3-yl H —C(O)OCH₂CH₃ φ- —CH₃ H—CH₂CH(CH₃)₂ H —C(O)NHCH₃ φ- —CH₃ H —CH₂-φ H —C(O)N(CH₃)₂ φ- —CH₃ H—CH₂CH(CH₃)₂ H —C(O)N(CH₃)₂ φ- —CH₃ H —CH(CH₃)₂ H —C(O)N(CH₃)₂ φ- —CH₃ H—CH₂-φ H —C(O)NHCH₃ φ- —CH₃ H —CH(CH₃)₂ H —C(O)NHCH₂ 3,5-di-F-φ- —CH₃ H—CH₂CH₂CH₂CH₃ H —C(O)NHCH₃ 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₂CH₃ H—C(O)N(CH₃)₂ 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₂CH₃ H —C(O)NH₂ 3,5-di-F-φ-—CH₃ H m-CH₃O-φ- H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H p-CH₃O-φ- H —C(O)OCH₃3,5-di-F-φ- —CH₃ H pyrid-2-yl H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ Hpyrid-4-yl H —C(O)OCH₂CH₃ cyclohexyl —CH₃ H —CH₂-φ H —C(O)OCH₃cyclopentyl —CH₃ H —CH₂-φ H —C(O)OCH₃ cyclohex-1-enyl —CH₃ H —CH₂-φ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H R⁴/R⁵ = -cyclopropyl —C(O)OCH₃ 3,5-di-F-φ-—CH₃ H —CH₃ H —C(O)N(CH₃)CH₂CH₂N(CH₃)₂ cyclopropyl —CH₃ H —CH₂φ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H H H —C(O)OCH₂-φ (CH₃)₂CH— -φ H —CH₃ H—C(O)OCH₂CH₃ 3-NO₂-φ- —CH₃ H —CH₂-φ H —C(O)OCH₃ 3-NO₂-φ- —CH₃ H —CH₃ H—C(O)OCH₂CH₃ 3-NO₂-φ- —CH₃ H H H —C(O)OCH₂CH₃ 3-NO₂-φ- —CH₃ H —CH(OH)CH₃H —C(O)NHOH (CH₃)₂CH— -φ H —CH₃ H —C(O)OCH₃CH(CH₃)₂ 3-NO₂-φ- —CH₃ Hm-hydroxybenzyl H —C(O)OCH₃ 3-NO₂-φ- —CH₃ H p-hydroxyhenzyl H—C(O)OCH₂CH₃ (CH₃)₂CH— —CH(CH₃)CH₂CH₃ H —CH₃ H —C(O)OCH₂CH(CH₃)₂(CH₃)₂CH— —CH₂-φ H —CH₃ H —C(O)OCH₂CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)OCH₂CH₃ 3-NO₂-φ- —CH₃ R₃/R₄ and N = H —C(O)OCH₂CH₃ 2,3-dihydro-indol-2-yl 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NH₂ (CH₃)₂CH— -φ H —CH₃ H—C(O)N(CH₃)—OCH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂CH(CH₃)₂3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)N(CH₂CH₂CH₃)₂ 3,5-di-F-φ- —CH₃ H—CH(CH₃)₂ H —C(O)NH₂ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NH-(p-NO₂-φ)3,5-di-F-φ- —CH₃ H —CH₂-φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-φ H—C(O)NH₂ (CH₃)₂CH— -φ H —CH₃ H —C(O)NHCH₂CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H—CH₂-φ H —C(O)NHCH₂CH₂OCH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)NHCH₂-(p-NO₂-φ) 3,5-di-F-φ- —CH₃ H —CH₂-φ H —C(O)NH-(p-NO₂-φ)3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)N(CH₃)CH₂-φ 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)NHCH₂-(3,5-di-F-φ) 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂(m-NO₂-φ)3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂-φ 3,5-di-F-φ- —CH₃ H —CH₂-φ H—C(O)NHCH₂-(p-NO₂-φ) 3,5-di-F-φ- —CH₃ H —CH₂-indol-3-yl H —C(O)OCH₃3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂-(p-OCH₃-φ) -φ -φ H —CH₃ H—C(O)OCH₂CH₃ cyclohexyl- -φ H —CH₃ H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ H -φH —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂CH₂-φ 3,5-di-F-φ- —CH₃ H—CH₂-indol-3-yl H —C(O)NH₂ 3,5-di-F-φ- —CH₃ H —CH₂-cyclohexyl H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H p-NO₂-benzyl- H —C(O)NHCH₂CH₂OCH₃ 3-NO₂-φ-—CH₃ H —CH₂OH H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH(CH₃)φ3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH(CH₃)φ 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)NHCH₂-(p-F-φ) 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂-(pyrid-4-yl)3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂-(p-F₃C-φ) 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ H —CH₂-φ H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃H —CH₃ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H cyclohexyl H —C(O)OCH₂CH₃3,5-di-F-φ- —CH₃ H -φ H —C(O)NHCH₂CH₂OCH₃ (CH₃)₂CH— cyclohexyl H —CH₃ H—C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHCH₂CH₂N(CH₃)₂ 3,5-di-F-φ-—CH₃ H -φ H —C(O)NHCH₂-(pyrid-2-yl) pyrid-3-yl —CH₃ H —CH₂-φ H —C(O)OCH₃pyrid-2-yl —CH₃ H —CH₂-φ H —C(O)OCH₃ pyrid-4-yl —CH₃ H —CH₂-φ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H p-F-φ H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ Ho-F-φ H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)OCH₂CH₃ 3,5-di-F-φ-—CH₃ H —CH₂—N-phthalimidyl H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ H p-F-φ H—C(O)OCH₂C(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)OCH₂C(CH₃)₃ 3,5-di-F-φ-—CH₃ H -φ H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)OC(CH₃)₃3,5-di-F-φ- —CH₃ H -φ H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NH₂3-NO₂-φ- —CH₃ H —CH(CH₃)₃ H —C(O)—N-morpholino 3-NO₂-φ- —CH₃ H —CH(CH₃)₃H —C(O)OCH₂CH₃ 3-NO₂-φ- —CH₃ H —CH(OH)CH₃ H —C(O)OCH₃ 3-NO₂-φ- —CH₃ H

H —C(O)—N-morpholino 3-NO₂-φ- —CH₃ H —CH(CH₃)CH₂CH₃ H —C(O)—N-morpholino3-NO₂-φ- —CH₃ H —CH(CH₃)CH₂CH₃ H —C(O)OCH₃ 3-NO₂-φ- —CH₃ H—CH(CH₃)CH₂CH₃ H —C(O)OH 3-NO₂-φ- —CH₃ H —CH₂CH₂CH₃ H —C(O)OCH₃ 3-NO₂-φ-—CH₃ H —CH₂CH(CH₃)₂ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂CH(CH₃)₂ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂CH₂OCH₃ 3,5-di-F-φ- —CH₃ H—CH₃ H —C(O)NHCH₂CH₂N(CH₃)₂ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NH-cyclohexyl3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂C(CH₃)₂ 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)NHCH₂-(tetra- hydrofuran-2-yl) 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)NHCH₂-(pyrid-2-yl) 3,5-di-F-φ- —CH₃ H —CH₃ H—C(O)—(N-thiazolidinyl) 3,5-di-F-φ- —CH₃ H —CH₂CH₃ H —C(O)OCH₃3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₃ H —C(O)OCH₃ 3,5-NO₂-φ- —CH₃ H —CH₂CH₃ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH(CH₃)CH₂CH₃ 3,5-di-F-φ-—CH₃ H —CH₃ H —C(O)—(N-pyrrolidinyl) 3,5-di-F-φ- —CH₃ H —CH(CH₃)₂ H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)NHCH₂CH₂—F 3,5-di-F-φ- —CH₃ H—CH₃ H —C(O)CH₂CH₂CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H —CH₂CH₃ H—C(O)NHCH₂-(p-NO₂-φ) 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₃ H—C(O)NHCH₂-(p-NO₂-φ) 3,5-di-F-φ- —CH₃ H m-F-φ- H —C(O)OCH₃ 3,5-di-F-φ-—CH₃ H thien-2-yl H —C(O)NH₂ 3,5-di-F-φ- —CH₃ H thien-2-yl H —C(O)NH₂3,5-di-F-φ- —CH₃ H 5-chlorobenzo[b]thiophen- H —C(O)OCH₃ 2-yl3,5-di-F-φ- —CH₃ H benzo[b]thiophen-6-yl H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃H benzo[b]thiophen-2-yl H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ Hbenzo[b]thiophen-2-yl H —C(O)OCH₂CH₃ 3,5-di-F-φ- —CH₃ Hbenzo[b]thiophen-3-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H thien-2-yl H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H benzo[b]thiophen-5-yl H —C(O)OCH₂CH₃3,5-di-F-φ- —CH₃ H thien-2-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H thien-2-ylH —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ H thien-2-yl H —C(O)OH 3,5-di-F-φ- —CH₃H tetrazol-5-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H 2-aminopyrid-6-yl H—C(O)OCH₃ 3,5-di-F-φ- —CH₃ H 6-methoxynaphth-2-yl H —C(O)OCH₃3,5-di-F-φ- —CH₃ H m-CF₃-φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H4,5,6,7-(tetrahydro- H —C(O)OCH₃ benzo[b]thiophen-2-yl 3,5-di-F-φ- —CH₃H thieno[2,3-b]thiophen-2-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H2-methylthiazol-4-yl H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂CH═CHCH₃ H—C(O)OCH₃ (trans) cyclopropyl —CH₃ H -φ H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃H (p-φ)-φ H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₂CH₃ H -φ H —C(O)OC(CH₃)₃3,5-di-F-φ- —CH(CH₃)₂ H -φ H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₂CH₂SCH₃ H -φH —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₂CH₃ H -φ H—C(O)OCH₃ 3,5-di-F-φ- —CH₂CH(CH₃)₂ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₂φ H-φ H —C(O)OCH₃ 3,5-di-F-φ- —H H -φ H —C(O)OCH₃ 3,5-di-F-φ- -φ H -φ H—C(O)OC(CH₃)₃ 3,5-di-F-φ- -φ H -φ H —C(O)OCH₃ φ- —CH₃ H —CH₃ H —C(O)OCH₃φ- —CH₃ H —CH₂CH(CH₃)₂ H —C(O)OCH₃ φ- —CH₃ H —CH(CH₃)CH₂CH₃ H —C(O)OCH₃φ- —CH₃ R₃/R₄ and N = H —C(O)OCH₃ L-pyrrolidinyl φ- —CH₃ H —CH₂-φ H—C(O)OCH₃ φ- —CH₃ H —(CH₂)₄NHC(O)O- H —C(O)OCH₃ t-butyl φ- —CH₃ H H H—C(O)OCH₃ φ- —CH₃ H —CH(CH₃)₂ H —C(O)OCH₃ φ- —CH₃ H —CH₂CH₃ H —C(O)OCH₃φ- —CH₃ H —CH₂CH₂CH₃ H —C(O)OCH₃ 3-NO₂-φ- —CH₃ H —CH(CH₃)₂ H —C(O)OH φ-—CH₃ —CH₃ —CH₃ H —C(O)OCH₃ (CH₃)₂CH— -φ H —CH₃ H —C(O)OCH₂CH(CH₃)₂(CH₃)₂CH— —CH(CH₃)CH₂CH₃ H —CH₃ H —C(O)OCH₂CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H-φ H —C(O)NH-cyclohexyl 3,5-di-F-φ- —CH₃ R³/R⁴ and N = H —C(O)OCH₂CH₃4-β-hydroxy- pyrrolidin-2-yl 3,5-di-F-φ- —CH₃ H —(CH₂)₄NH₂ H —C(O)OCH₃3,5-di-F-φ- —CH₃ H —CH₂CH₂C(O)NH₂ H —C(O)NH₂ 3,5-di-F-φ- —CH₃ R₃/R₄ andN = H —C(O)OCH₃ piperidin-2-yl 3,5-di-F-φ- —CH₃ H H H —C(O)NHCH₂CH₂OCH₃3,5-di-F-φ- -cyclohexyl H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H —CH₂-φ H—C(O)NHCH₂-pyrid-2-yl 3,5-di-F-φ- -thien-2-yl H -φ H —C(O)OC(CH₃)₃3,5-di-F-φ- φ H -φ H —C(O)NH₂ 3,5-di-F-φ- —CH(CH₃)₂ H -φ H —C(O)NH₂-thienyl —CH₃ H -φ H —C(O)NH₂ CH₃(CH₂)₂— —CH₃ H -φ H —C(O)NH₂3,5-di-F-φ- —(CH₂)₃CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —(CH₂)₂CH₃ H -φ H—C(O)OCH₃ 3,5-di-F-φ- —C(CH₂)₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ-—C(CH₃)CH₂CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₂φ H -φ H —C(O)OCH₃3,5-di-F-φ- -cyclopropyl H -φ H —C(O)OCH₃ 3,5-di-F-φ- -thien-3-yl H -φ H—C(O)OCH₃ 3,5-di-F-φ- -thien-2-yl H -φ H —C(O)OCH₃ 3,5-di-F-φ- p-F-φ H-φ H —C(O)OCH₃ 3,5-di-F-φ- p-OCH₃-φ H -φ H —C(O)OCH₃ 3,5-di-F-φ- -φ H -φH —C(O)OC(CH₃)₃ -cyclopropyl -φ H -φ H —C(O)OC(CH₃)₃ -cyclopenyl -φ H -φH —C(O)OC(CH₃)₃ —C(CH₃)₃ —CH₃ H -φ H —C(O)NH₂ 3,5-di-F-φ- —CH₃ H5-bromothien-2-yl H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H 4-bromothien-2-ylH —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H thien-2-yl H —C(O)NHC(CH₃)₃3,5-di-F-φ- —CH₃ H thien-3-yl H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H 5-chlorothien-2-yl H —C(O)NHC(CH₃)₃3,5-di-F-φ- —CH₃ H (p-φ)-φ- H —C(O)NH-cyclohexyl 3,5-di-F-φ- —CH₃ H(m-phenoxy)-φ- H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH-cyclohexyl 3,5-di-F-φ- —CH₃ H (m-φ)-φ- H —C(O)NHC(CH₃)₃3,5-di-F-φ- —CH₃ H (p-CH₃CH₂)-φ- H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H(o-φ)-φ- H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H (o-benzyl)-φ- H—C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H (p-Br)-φ- H —C(O)NHC(CH₃)₃ 3,5-di-F-φ-—CH₃ H (p-φ)-φ- H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H (p-CH₃CH₂φ)-φ- H—C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H (p-tert-butyl)-φ- H —C(O)NHC(CH₃)₃3,5-di-F-φ- —CH₃ H o-(4-Cl-phenoxy)-φ- H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃H (p-φ)-φ- H —C(O)NH-cyclohexyl 3,5-di-F-φ- —CH₃ H -φ H —C(O)OC(CH₃)₃3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)-φ 3,5-di-F-φ- —CH₃ H pyrid-3-yl H—C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)-morpholino 3,5-di-F-φ- —CH₃H (m-methoxy)-φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)ONHC(O)OC(CH₃)₃3,5-di-F-φ- —CH₃ H -φ H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHCH₂-furan-2-yl 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHOCH₃ 3,5-di-F-φ-—CH₃ H -φ H —C(O)-cyclobutylamide 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHCH₂CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHCH₂-cyclopropyl3,5-di-F-φ- —CH₃ H -φ H —C(O)N(CH₃)OCH₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHCH₂C(CH₃)═CH₂ 3,5-di-F-φ- —CH₃ H -φ H —C(O)CH₂-pyrid-3-yl3,5-di-F-φ- —CH₃ H -φ H —C(O)CH₂-pyrid-4-yl 3,5-di-F-φ- —CH₃ H -φ H—C(O)CH₂-fur-2-yl 3,5-di-F-φ- —CH₃ H -φ H —C(O)NH-cyclopentyl3,5-di-F-φ- —CH₃ H -φ H —C(O)NH-[(p-benzyl)-pyrid-4-yl] 3,5-di-F-φ- —CH₃H -φ H —C(O)N(CH₃)₂ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH-[2,6-dimethylpyrid-4- yl] 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH-(2-methylcyclohexyl) 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH-(4-methylcyclohexyl) 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH—[N-ethoxycarbonyl]- piperidin-4-yl 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHCH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHOC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φH —C(O)ONHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHNH₂ 3,5-di-F-φ- —CH₃ H-φ H —C(O)NHN═C(CH₃)OCH₂CH₃ -φ —CH₃ H -φ H —C(O)OC(CH₃)₃ 3,5-di-F-φ-—CH₃ H -φ H —C(O)NH(CH₂)₄-φ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH(CH₂)₃O(p-CH₃)φ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NH(CH₂)₆NH₂3,5-di-F-φ- 3,5-di-F-φ- H 3,5-di-F-φ- H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H—CH₂CH₂CH₂CH₃ H —C(O)OH -cyclopentyl —CH₃ H -φ H —C(O)OC(CH₃)₃3,5-di-F-φ- thien-2-yl H -φ H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ R₃/R₄ and N= H —C(O)OCH₃ L-(3-α-phenyl)- pyrrolidinyl 3,5-di-F-φ- —CH₃ R₃/R₄ and N= H —C(O)OCH₃ L-azetidin-2-yl 3,5-di-F-φ —CH₃ H5-chlorobenzo[b]thiophen- H —C(O)OCH₃ 3-yl 3,5-di-F-φ- —CH₃ H—CH₂-thiazol-4-yl H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHC(CH₃)₃3,5-di-F-φ- —CH₃ H thien-2-yl H —C(O)NH₂ 3,4-di-Cl-φ- —CH₃ H -φ H—C(O)NH₂ 3-Cl-φ- —CH₃ H -φ H —C(O)NH₂ 3-Br-φ- —CH₃ H -φ H —C(O)NH₂3-F-φ- —CH₃ H -φ H —C(O)NH₂ 4-F-φ- —CH₃ H -φ H —C(O)NH₂ 3-CH₃-φ- —CH₃ H-φ H —C(O)NH₂ 4-CH₃-φ- —CH₃ H -φ H —C(O)NH₂ 3-CF₃-φ- —CH₃ H -φ H—C(O)NH₂ 3-CH₃O-φ- —CH₃ H -φ H —C(O)NH₂ 2-Cl-φ- —CH₃ H -φ H —C(O)NH₂1-naphthyl —CH₃ H -φ H —C(O)NH₂ 2-naphthyl —CH₃ H -φ H —C(O)NH₂ φ- —CH₃H -φ H —C(O)NH₂ 3,5-di-F-φ- —CH₃ H -φ H —COOH 3,5-di-F-φ- —CH₃ Hfuran-2-yl H —C(O)NH₂ 3,4-di-F-φ- —CH₃ H -φ H —C(O)NH₂ 3,5-di-F-φ- —CH₃H —CH₂-φ H —C(O)NH—SO₂—CH₃ 3,5-di-F-φ- —CH₃ H H H —C(O)N(CH₃)φ3,5-di-F-φ- —CH₃ H —CH₃ H —C(O)N(CH₃)φ 3,5-di-F-φ- —CH₂CH₂SCH₃ H -φ H—C(O)NH₂ 3,5-di-F-φ- —CH₃ H H H —C(O)N(CH₃)CH₂φ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHCH₂(p-F-φ) 3,5-di-F-φ- —CH₃ H 4-fluorophenyl H —C(O)OCH₂C(CH₃)₃2,3,4,5,6-penta-F-φ- —CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₂OCH₂-φ H -φ H—C(O)OCH₃ 3,5-di-F-φ- —CH(CH₃)OCH₂-φ H -φ H —C(O)OCH₃ 3,5-di-F-φ-—CH(OH)CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₂OH H -φ H —C(O)OCH₃3,5-di-F-φ- —CH₃ H -φ H —C(O)NH-(4-methylphenyl) 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH-2-tetrahydrofurfuryl 3,5-di-F-φ- —CH₃ H 4-fluoro-φ H —C(O)NH₂3,5-di-F-φ- —CH₂CH₂SCH₃ H -φ H —C(O)NH₂ 3,5-di-F-φ- —CH₂CH₃ H -φ H—C(O)NH₂ 3,5-di-F-φ- -φ H -φ H —C(O)NH₂ 3,5-di-F-φ- —CH(CH₃)₂ H -φ H—C(O)NH₂ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NHCH(CH₃)φ 3,5-di-F-φ- —CH₃ H -φ H—C(O)CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H -φ H —C(O)CH₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)CH₂CH₂CH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)-φ 3,5-di-F-φ- —CH₃ H -φ H—C(O)CH₂CH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)CH₂CH(CH₃)₂ 3,5-di-F-φ- —CH₃ H-φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)NH(CH₂)₄NHC(O)-(2-hydroxy-4-azido)- phenyl 3,5-di-F-φ- —CH₃ H 4-fluoro-φ H—C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃ H 4-φ-φ- H —C(O)OC(CH₃)₃ 3,5-di-F-φ- —CH₃R₃/R₄ and N = H —C(O)OCH₃ 3,3-dihydro- 2-isobenzazolyl 3,5-di-F-φ- —CH₃H 4-n-butylphenyl H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H4-phenylacetylenylphenyl H —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H—C(S)NH₂ 3,5-di-F-φ- —CH₃ H -φ H —C(O)CH₂-φ 3,5-di-F-φ- —CH₃ H -φ H—C(O)-cyclopentyl 3,5-di-F-φ- —CH₃ H -φ H —C(O)-n-butyl 3,5-di-F-φ- —CH₃H -φ H —C(O)CH(CH₃)CH₂CH₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NH(CH₂)₆-(biotinamidyl) 3,5-di-F-φ- —CH₂CH₂SCH₃ H —CH₂CH₂SCH₃ H—C(O)OCH₃ t-BOC—NH—CH₂— —CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- —CH₃ H -φ H—C(O)NHC(CH₃)₃ 3,5-di-F-φ- —CH₃ H -φ H —C(O)OCH₃ 3,5-di-F-φ- thien-3-ylH -φ H —C(O)OH 3,5-di-F-φ- thien-3-yl H -φ H —C(O)OC(CH₃)₃(2,5-di-Cl-φ)-O— —CH₃ H -φ H —C(O)OCH₃ (3,5-di-F-φ)-O— —CH₃ H -φ H—C(O)OCH₃ (3,4-di-Cl-φ)-S— —CH₃ H -φ H —C(O)OCH₃

R¹ R² R³ R⁴ Y′ Y″ 3,5-di-F-φ- —CH₃ H —CH₂φ —CH₂C(O)OCH₃ H 3,5-di-F-φ-—CH₃ H —CH₃ —CH₂CH₂CH(CH₃)₂ H 3,5-di-F-φ- —CH₃ H -φ H H 3,5-di-F-φ- —CH₃H —CH₂φ H H 3,5-di-F-φ- —CH₃ H —CH₃ H H 3,5-di-F-φ- —CH₃ H —CH₃ -φ H3,5-di-F-φ- —CH₃ H -φ -φ H 3,5-di-F-φ- —CH₃ H —(CH₂)₃CH₃ H H 3,5-di-F-φ-—CH₃ H —CH₂-(p- H H hydroxyphenyl) 3,5-di-F-φ- —CH₃ H 2-pyridyl H H3,5-di-F-φ- —CH₃ H 4-pyridyl H H 3,5-di-F-φ- —CH₃ H —CH₂CH(CH₃)₂ H H3,5-di-F-φ- —CH₃ H —CH(CH₃)₂ H H 3,5-di-F-φ- —CH₃ H —CH₃ H H 3,5-di-F-φ-—CH₃ H thien-2-yl H H 3,5-di-F-φ- —CH₃ H -φ —CH₃ —CH₃ 3,5-di-F-φ- -φ H-φ H H -cyclopropyl -φ H -φ H H -cyclopentyl -φ H -φ H H

R¹ R² R³ R⁴ Q Y′ 3,5-di-F-φ- —CH₃ H —CH₃ —OCH₃ H 3,5-di-F-φ- —CH₃ H -φ—OCH₃ H 3,5-di-F-φ- —CH₃ H —CH₂φ —OCH₃ H 3,5-di-F-φ- —CH₃ H—CH₂CH₂CH₂CH₃ —OC(O)CH₃ H 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₂CH₃ —OC(O)C(CH₃)₃H 3,5-di-F-φ- —CH₃ H —CH₂CH₂CH₃ -phthalimido H

R¹ R² R^(4′) R⁴ X (CH₃)₂CH— (CH₃)₂CH— -φ —CH₃ —C(O)OCH₂CH(CH₃)₂(CH₃)₂CH— -φ —CH₃ —CH₂-φ —C(O)NH₂ (CH₃)₂CH -φ —CH₃ —CH₃ —C(O)NH(p-NO₂-φ)3,5-di-F-φ- —CH₃ —CH₂-φ -φ —C(O)OCH₃ 3,5-di-F-φ- —CH₃ —CH₃ -φ —C(O)OCH₃3-NO₂-φ- —CH₃ —CH(OH)CH₃ —CH(CH₃)₂ —C(O)OCH₂CH₃ 3,5-di-F-φ- -φ —CH₃ -φ—CH₂OH 3,5-di-F-φ- —CH₃ -φ H —CH₂OH

R¹ X′ X″ R² R⁴ X 3,5-di-F-φ- —OH H —CH₃ -φ —C(O)NHC(CH₃)₃ 3,5-di-F-φ- —FF —CH₃ -φ —C(O)NHC(CH₃)₃ 3,5-di-F-φ- X′/X″ = —CH₃ -φ —C(O)OC(CH₃)₃ = O

DETAILED DESCRIPTION OF THE INVENTION

[0506] As above, this invention relates to methods for inhibitingβ-amyloid peptide release and/or its synthesis, and, accordingly, haveutility in treating Alzheimer's disease. However, prior to describingthis invention in further detail, the following terms will first bedefined.

[0507] Definitions

[0508] The term “β-amyloid peptide” refers to a 39-43 amino acid peptidehaving a molecular weight of about 4.2 kD, which peptide issubstantially homologous to the form of the protein described byGlenner, et al.¹ including mutations and post-translationalmodifications of the normal β-amyloid peptide. In whatever form, theβ-amyloid peptide is an approximate 39-43 amino acid fragment of a largemembrane-spanning glycoprotein, referred to as the β-amyloid precursorprotein (APP). Its 43-amino acid sequence is: 1 Asp Ala Glu Phe Arg HisAsp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Ala GluAsp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly ValVal 41 Ile Ala Thr (SEQ ID NO: 1)

[0509] or a sequence which is substantially homologous thereto.

[0510] “Alkyl” refers to monovalent alkyl groups preferably having from1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, n-hexyl, and the like.

[0511] “Substituted alkyl” refers to an alkyl group, preferably of from1 to 10 carbon atoms, having from 1 to 3 substituents selected from thegroup consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy,heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters,cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl,oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl,heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- anddi-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetricdi-substituted amines having different substituents selected from alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic.

[0512] “Alkylene” refers to divalent alkylene groups preferably havingfrom 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Thisterm is exemplified by groups such as methylene (—CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—),and the like.

[0513] “Alkaryl” refers to -alkylene-aryl groups preferably having from1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbonatoms in the aryl moiety. Such aLkryl groups are exemplified by benzyl,phenethyl and the like.

[0514] “Alkoxy” refers to the group “alkyl-O-”. Preferred alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

[0515] “Substituted alkoxy” refers to the group “substituted alkyl-O-”where substituted alkyl is as defined above.

[0516] “Alkylalkoxy” refers to the group “-alkylene-O-alkyl” wherealkylene and alkyl are as defined above. Such groups include, by way ofexample, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃),n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)2), methylene-t-butoxy(—CH₂—O—C(CH₃)₃) and the like.

[0517] “Alkylthioalkoxy” refers to the group “-alkylene-S-alkyl” whereinalkylene and alkyl are as defined above. Such groups include, by way ofexample, methylthiomethoxy (—CH₂SCH₃), ethylthiomethoxy (—CH₂CH₂SCH₃),n-propyl-iso-thiopropoxy (—CH₂CH₂CH₂SCH(CH₃)₂), methylthio-t-butoxy(-CH₂SC(CH₃)₃) and the like.

[0518] “Alkenyl” refers to alkenyl groups preferably having from 2 to 10carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation. Preferredalkenyl groups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂),iso-propenyl (—C(CH₃)═CH₂), but-2-enyl (—CH₂CH═CHCH₃), and the like.

[0519] “Substituted alkenyl” refers to an alkenyl group as defined abovehaving from 1 to 3 substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl,aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl,cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substitutedthioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic.

[0520] “Alkynyl” refers to alkynyl groups preferably having from 2 to 10carbon atoms and more preferably 2 to 6 carbon atoms and having at least1 and preferably from 1-2 sites of alkynyl unsaturation. Preferredalkynyl groups include ethynyl (—CH≡CH₂), propargyl (—CH₂C≡CH) and thelike.

[0521] “Substituted alkynyl” refers to an alkynyl group as defined abovehaving from 1 to 3 substituents selected from the group consisting ofalkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl,aminocarboxy esters, cyano, halogen, hydroxyl, earboxyl, carboxylalkyl,cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substitutedthioalkyoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic.

[0522] “Acyl” refers to the groups alkyl-C(O)—, substituted alkyl-C(O)—,cycloalkyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)— and heterocyclic-C(O)—where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[0523] “Acylamino” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl,heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0524] “Aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl,heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0525] “Oxyacyl” refers to the groups —OC(O)-alkyl, —OC(O)-aryl, —C(O)O—heteroaryl-, and —C(O)O-heterocyclic where alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[0526] “Oxyacylamino” refers to the groups —OC(O)NR-alkyl, —OC(O)NR—substituted alkyl, —OC(O)NR-aryl, —OC(O)NR-heteroaryl-, and—OC(O)NR—heterocyclic where R is hydrogen, alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are asdefined herein.

[0527] “Aminocarboxy esters” refers to the groups —NRC(O)O-alkyl,—NRC(O)O-substituted alkyl, —NRC(O)O-aryl, —NRC(O)O-heteroaryl, and—NRC(O)O-heterocyclic where R is hydrogen, alkyl, substituted alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are asdefined herein.

[0528] “Aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 14 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed rings (e.g., naphthyl or anthryl). Preferred arylsinclude phenyl, naphthyl and the like.

[0529] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with from 1to 5 and preferably 1 to 3 substituents selected from the groupconsisting of hydroxy, biotinamidyl, acyl, alkyl, alkoxy, alkenyl,alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl,substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl,aryl, aryloxy, azido, carboxyl, carboxylalkyl, acylamino, cyano, halo,nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy,substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- anddi-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetricdi-substituted amines having different substituents selected from alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic, and the like.Preferred substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy.

[0530] “Aryloxy” refers to the group aryl-O- wherein the aryl group isas defined above including optionally substituted aryl groups as alsodefined above.

[0531] The term “carboxy terminal R⁴ group” refers to that R⁴ group incompounds of formula I which, when n is two, is closest to the X group.

[0532] Carboxyalkyl” refers to the groups —C(O)O-alkyl and —C(O)O—substituted alkyl where alkyl and substituted alkyl are as definedabove.

[0533] “Cycloal” refers to cyclic alkyl groups of from 3 to 10 carbonatoms having a single cyclic ring or multiple condensed rings which canbe optionally substituted with from 1 to 3 alkyl groups. Such cycloalkylgroups include, by way of example, single ring structures such ascyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ringstructures such as adamantanyl, and the like.

[0534] “Cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 8carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation which can be optionally substituted with from I to3 alkyl groups. Examples of suitable cycloalkenyl groups include, forinstance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and thelike.

[0535] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is either chloro or bromo.

[0536] “Heteroaryl” refers to a monovalent aromatic group of from 2 to10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogenand sulfur within the ring.

[0537] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 3 substituents selected from the group consisting of hydroxy, acyl,alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy,substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxyesters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl,cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino,thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- anddi-alkylamino, mono- and di-(substituted alkyl)amino, mono- anddi-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclicamino, and unsymmetric di-substituted amines having differentsubstituents selected from alkyl, substituted alkyl, aryl, heteroaryland heterocyclic, and the like. Preferred substituents include alkyl,alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

[0538] Such heteroaryl groups can have a single ring (e.g., pyridyl orfuryl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).Preferred heteroaryls include pyridyl, pyrrolyl and furyl.

[0539] “Heteroaryloxy” refers to the group heteroaryl-O- wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

[0540] “Heterocycle” or “heterocyclic” refers to a monovalent (i.e., onepoint of attachment) saturated or unsaturated group having a single ringor multiple condensed rings, from 1 to 8 carbon atoms and from 1 to 4hetero atoms selected from nitrogen, sulfur or oxygen within the ring.

[0541] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 4 substituents selected from the group consistingof hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl, amino,aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl,carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic,oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy,trihalomethyl, mono- and di-alkylamino, mono- and di-(substitutedalkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono-and di-heterocyclic amino, and unsymmetric di-substituted amines havingdifferent substituents selected from alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic, and the like. Such heterocyclic groups canhave a single ring or multiple condensed rings. Preferred heteroarylsinclude morpholino, piperidinyl, and the like.

[0542] Examples of heterocycles and heteroaryls include, but are notlimited to, furan, thiophene, thiazole, oxazole, pyrrole, imidazole,pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine,isoindole, indole, indazole, purine, quinolizine, isoquinoline,quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline,cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzob]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

[0543] “Heterocyclyloxy” refers to the group heterocyclyl-O- wherein theheterocyclic group is as defined above including optionally substitutedheterocyclic groups as also defined above.

[0544] “Oxyacyl” refers to the groups —OC(O)-alkyl, —OC(O)-aryl,—C(O)O—heteroaryl-, and —C(O)O-heterocyclic where alkyl, aryl,heteroaryl and heterocyclic are as defined herein.

[0545] “Oxyacylarmino” refers to the groups —OC(O)NH-alkyl,—OC(O)NH-substituted alkyl, —OC(O)NH-aryl, —OC(O)NH-heteroaryl-, and—OC(O)NH-heterocyclic where alky, aryl, heteroaryl and heterocyclic areas defined herein.

[0546] “Thiol” refers to the group —SH.

[0547] “Thioalkoxy” refers to the group —S-alkyl.

[0548] “Substituted thioalkoxy” refers to the group -S-substitutedalkyl.

[0549] “Thioaryloxy” refers to the group aryl-S- wherein the aryl groupis as defined above including optionally substituted aryl groups alsodefined above.

[0550] “Thioheteroaryloxy” refers to the group heteroaryl-S- wherein theheteroaryl group is as defined above including optionally substitutedaryl groups as also defined above.

[0551] “Pharmaceutically acceptable salt” refers to pharmaceuticallyacceptable salts of a compound of Formula I which salts are derived froma variety of organic and inorganic counter ions well known in the artand include, by way of example only, sodium, potassium, calcium,magnesium, ammonium, tetraalkylammonium, and the like; and when themolecule contains a basic functionality, salts of organic or inorganicacids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate,maleate, oxalate and the like.

[0552] Compound Preparation

[0553] The compounds of formula I are readily prepared via severaldivergent synthetic routes with the particular route selected relativeto the ease of compound preparation, commercial availability of startingmaterials, etc.

[0554] A first synthetic method involves conventional coupling of anacetic acid derivative with a primary amine of an esterified amino acidas shown in reaction (1) below:

[0555] wherein R¹, R², R³, X′ and X″ are as defined above, and X iseither oxygen or —NH—.

[0556] Reaction (1) merely involves coupling of a suitable acidderivative 1 with the primary amine of amino acid ester 2 underconditions which provide for the N-acetyl derivative 3. This reaction isconventionally conducted for peptide synthesis and synthetic methodsused therein can also be employed to prepare the N-acetyl amino acidesters 3 of this invention. For example, well known coupling reagentssuch as carbodiimides with or without the use of well known additivessuch as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be usedto facilitate coupling. The reaction is conventionally conducted in aninert aprotic diluent such as dimethylformamide, dichloromethane,chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively,the acid halide of compound 1 can be employed in reaction (1) and, whenso employed, it is typically employed in the presence of a suitable baseto scavenge the acid generated during the reaction. Suitable basesinclude, by way of example, triethylamine, diisopropylethylamine,N-methylmorpholine and the like.

[0557] Reaction (1) is preferably conducted at from about 0° C. to about60° C. until reaction completion which typically occurs within 1 toabout 24 hours. Upon reaction completion, N-acetyl amino acid ester 3 isrecovered by conventional methods including precipitation,chromatography, filtration and the like or alternatively is hydrolyzedto the corresponding acid without purification and/or isolation otherthan conventional work-up (e.g., aqueous extraction, etc.).Alternatively, the synthesis described above in reaction (1) can beconducted on the amino acid (XR³═OH) and subsequent to N-acetylformation as described above.

[0558] In any event, if an N-acetyl amino acid ester is formed, it isconverted to the corresponding acid prior to the coupling step withanother amino acid ester/amide, HNR³CR⁴R⁵C(O)Y. Coupling is accomplishedusing well known peptide coupling chemistry with well known couplingreagents such as carbodiimides with or without the use of well knownadditives such as N-hydroxysuccinimide, l-hydroxybenzotriazole, etc.which can be used to facilitate coupling. The reaction is conventionallyconducted in an inert aprotic polar diluent such as dimethylformamide,dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.

[0559] Such coupling yields compounds of formula I where n is 1. Thesynthesis of compounds of formula I where n is 2 is accomplished via asecond coupling reaction. Specifically, in the first coupling reaction,HNR³CR⁴R⁵C(O)Y is selected to be an amino acid ester. That is to saythat Y is —O-alkyl. After coupling, the ester is hydrolyzed viaconventional conditions well known in the art to provide for thecorresponding carboxylic acid which can now be used to couple a secondamino acid ester/amide.

[0560] In reaction (1), each of the reagents (compound 1 and amino acidester 2) are well known in the art with a plurality of each beingcommercially available.

[0561] Alternatively, the compounds of formula I can be prepared byfirst forming the dipeptide ester and then N-acylating these esters.That is to say that the amino acid ester or amide HNR³CR⁴R⁵C(O)Y iscoupled to the N-blocked amino acid BlockNHCHR²COOH via conventionalcoupling conditions to provide for the dipeptideBlockNHCHR²C(O)N(R³)CR⁴R⁵C(O)Y. The blocking group is then removed viaconventional conditions to provide for the free amine which is thenN-acylated in the manner described above to provide for the compounds offormula I.

[0562] After coupling and N-acylation (in whatever order) is complete,the resulting esters and amides can be derivatized via conventionalchemistry to provide for derivatives of the synthesized compounds. Forexample, conventional reduction of a terminal ester group with lithiumborohydride leads to the terminal —CH₂OH group. Alternatively, an estergroup can be converted to a primary amide [—C(O)NH₂] by reaction withammonia in methanol with a catalytic amount of sodium cyanide whileheating.

[0563] Similarly, reactive functionality which is blocked on either R²and/or R³ groups can be deblocked and then derivatized. For example, thea BOC protected amino group on R³ (e.g., lysine side chain) can bedeblocked after synthesis and the amino group acylated or otherwisedderivatized.

[0564] Additionally, a terminal ester can be subjected totransesterification techniques to provide for other esters. Numeroustechniques are known in the art to effect transesterification and eachtechnique merely replaces one ester group with a different ester groupderived from the corresponding alcohol or thioalcohol and, in somecases, a catalyst such as titanium (IV) iso-propoxide is used tofacilitate reaction completion. In one technique, the alcohol orthioalcohol is first treated with sodium hydride in a suitable diluentsuch as toluene to form the corresponding sodium alkoxide orthioalkoxide which is then employed to effect transesterification. Theefficiency of this technique makes it particularly useful with highboiling and/or expensive alcohols or thioalcohols.

[0565] In another transesterification technique, the ester to betransesterified is placed in a large excess of the alcohol orthioalcohol which effects transesterification. A catalytic amount ofsodium hydride is then added and the reaction proceeds quickly underconventional conditions to provide the desired transesterified product.Because this protocol requires the use of a large excess of alcohol orthioalcohol, this procedure is particularly useful when the alcohol orthioalcohol is inexpensive.

[0566] Transesterification provides a facile means to provide for amultiplicity of different ester substituents on the compounds of formulaI above. In all cases, the alcohols and thioalcohols employed to effecttransesterification are well known in the art with a significant numberbeing commercially available.

[0567] Other methods for preparing the esters of this invention include,by way of example, first hydrolyzing the ester to the free acid followedby O-alkylation with a halo-R³ group in the presence of a base such aspotassium carbonate. Alternatively, for esterification procedures foralcohols containing an ester group can be achieved by using the methodsof Losse, et al.¹¹

[0568] The compounds described herein can also be prepared by use ofpolymer supported forms of carbodiimide peptide coupling reagents. Apolymer supported form of EDC, for example, has been described(Tetrahedron Letters, 34(48), 7685 (1993))¹⁰. Additionally, a newcarbodiimide coupling reagent, PEPC, and its corresponding polymersupported forms have been discovered and are very useful for thepreparation of the compounds of the present invention.

[0569] Polymers suitable for use in making a polymer supported couplingreagent are either commercially available or may be prepared by methodswell known to the artisan skilled in the polymer arts. A suitablepolymer must possess pendant sidechains bearing moieties reactive withthe terminal amine of the carbodiimide. Such reactive moieties includechioro, bromo, iodo and methanesulfonyl. Preferably, the reactive moietyis a chloromethyl group. Additionally, the polymer's backbone must beinert to both the carbodiimide and reaction conditions under which theultimate polymer bound coupling reagents will be used.

[0570] Certain hydroxymethylated resins may be converted intochloromethylated resins useful for the preparation of polymer supportedcoupling reagents. Examples of these hydroxylated resins include the4-hydroxymethyl-phenylacetamidomethyl resin (Pam Resin) and4-benzyloxybenzyl alcohol resin (Wang Resin) available from AdvancedChemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994catalog, page 115). The hydroxymethyl groups of these resins may beconverted into the desired chloromethyl groups by any of a number ofmethods well known to the skilled artisan.

[0571] Preferred resins are the chloromethylated styrene/divinylbenzeneresins because of their ready commercial availability. As the namesuggests, these resins are already chloromethylated and require nochemical modification prior to use. These resins are commercially knownas Merrifield's resins and are available from Aldrich Chemical Companyof Milwaukee, Wis., USA (see Aldrich 1994-1995 catalog, page 899).Methods for the preparation of PEPC and its polymer supported forms areoutlined in the following scheme.

[0572] Such methods are described more fully in U.S. patent applicationSer. No. 60/019,790 filed Jun. 14, 1996 which application isincorporated herein by reference in its entirety. Briefly, PEPC isprepared by first reacting ethyl isocyanate with1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with4-toluenesulfonyl chloride to provide PEPC. The polymer supported formis prepared by reaction of PEPC with an appropriate resin under standardconditions to give the desired reagent.

[0573] The carboxylic acid coupling reactions employing these reagentsare performed at about ambient temperature to about 45° C., for fromabout 3 to 120 hours. Typically, the product may be isolated by washingthe reaction with CHCl₃ and concentrating the remaining organics underreduced pressure. As discussed supra, isolation of products fromreactions where a polymer bound reagent has been used is greatlysimplified, requiring only filtration of the reaction mixture and thenconcentration of the filtrate under reduced pressure.

[0574] Still other methods for the preparation of esters are provided inthe examples below.

[0575] Compounds where X is —CR⁶R⁶Y′ are readily prepared by coupling,e.g., an amino alcohol H₂NCR⁴R⁵CR⁶R⁶OH, to the carboxyl group ofR¹ZCX′X″C(O)NHCHR²C(O)OH under standard coupling conditions well knownin peptide coupling chemistry which can use well known coupling reagentssuch as carbodiimides with or without the use of well known additivessuch as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. If necessary,well known blocking groups on Y′ can be employed to protect the groupduring coupling. Such blocking groups are particularly desirable when Y′is an amino group.

[0576] The reaction is conventionally conducted in an inert aproticpolar diluent such as dimethylformamide, dichloromethane, chloroform,acetonitrile, tetrahydrofuran and the like. Upon reaction completion,any blocking groups on Y′ are selectively removed to provide for thedesired compound.

[0577] When Y′ is —OH or —SH, post-synthetic conversion of these groupsto the corresponding esters (i.e., —OC(O)R⁷), disulfides (i.e., —SSR⁷)and —SSC(O)R⁷ groups is accomplished using well known chemistry. Forexample, ester synthesis requires only reaction with a suitable acidsuch as acetic acid (R⁷=methyl), acid halide (e.g., acid chloride) oracid anhydride under suitable esterification conditions.

[0578] When one of R⁶ is hydrogen, post-synthetic oxidation of the—CHR⁶OH group leads to the ketone derivatives. Alternatively, suchketones can be prepared by coupling the suitable aminoketone HCl saltwith the terminal carboxyl group of the amino acid as illustrated inExample 168 below.

[0579] In these synthetic methods, the starting materials can contain achiral center (e.g., alanine) and, when a racemic starting material isemployed, the resulting product is a mixture of R,S enatiomers.Alternatively, a chiral isomer of the starting material can be employedand, if the reaction protocol employed does not racemize this startingmaterial, a chiral product is obtained. Such reaction protocols caninvolve inversion of the chiral center during synthesis.

[0580] Accordingly, unless otherwise indicated, the products of thisinvention are a mixture of R,S enatiomers or diasteriomers. Preferably,however, when a chiral product is desired, the chiral productcorresponds to the L-amino acid derivative. Alternatively, chiralproducts can be obtained via purification techniques which separateenatiomers from a R,S mixture to provide for one or the otherstereoisomer. Such techniques are well known in the art.

[0581] Pharmaceutical Formulations

[0582] When employed as pharmaceuticals, the compounds of formula I areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

[0583] This invention also includes pharmaceutical compositions whichcontain, as the active ingredient, one or more of the compounds offormula I above associated with pharmaceutically acceptable carriers. Inmaking the compositions of this invention, the active ingredient isusually mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier which can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

[0584] In preparing a formulation, it may be necessary to mill theactive compound to provide the appropriate particle size prior tocombining with the other ingredients. If the active compound issubstantially insoluble, it ordinarily is milled to a particle size ofless than 200 mesh. If the active compound is substantially watersoluble, the particle size is normally adjusted by milling to provide asubstantially uniform distribution in the formulation, e.g. about 40mesh.

[0585] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents. The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart.

[0586] The compositions are preferably formulated in a unit dosage form,each dosage containing from about 5 to about 100 mg, more usually about10 to about 30 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient. Preferably, the compound of formula I above isemployed at no more than about 20 weight percent of the pharmaceuticalcomposition, more preferably no more than about 15 weight percent, withthe balance being pharmaceutically inert carrier(s).

[0587] The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

[0588] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

[0589] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action. For example, the tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over the former; The two components can separated by entericlayer which serves to resist disintegration in the stomach and permitthe inner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

[0590] The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

[0591] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

[0592] The following formulation examples illustrate the pharmaceuticalcompositions of the present invention.

FORMULATION EXAMPLE 1

[0593] Hard gelatin capsules containing the following ingredients areprepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[0594] The above ingredients are mixed and filled into hard gelatincapsules in 340 mg quantities.

FORMULATION EXAMPLE 2

[0595] A tablet formula is prepared using the ingredients below:Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0596] The components are blended and compressed to form tablets, eachweighing 240 mg.

FORMULATION EXAMPLE 3

[0597] A dry powder inhaler formulation is prepared containing thefollowing components: Ingredient Weight % Active Ingredient 5 Lactose 95

[0598] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

FORMULATION EXAMPLE 4

[0599] Tablets, each containing 30 mg of active ingredient, are preparedas follows: Quantity Ingredient (mg/tablet) Active Ingredient  30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate  0.5 mg Talc  1.0 mg Total  120 mg

[0600] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which arethen passed through a 16 mesh U.S. sieve. The granules so produced aredried at 50° to 60° C. and passed through a 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

FORMULATION EXAMPLE 5

[0601] Capsules, each containing 40 mg of medicament are made asfollows: Quantity Ingredient (mg/capsule) Active Ingredient  40.0 mgStarch 109.0 mg Magnesium stearate  1.0 mg Total 150.0 mg

[0602] The active ingredient, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

[0603] Suppositories, each containing 25 mg of active ingredient aremade as follows: Ingredient Amount Active Ingredient   25 mg Saturatedfatty acid glycerides to 2,000 mg

[0604] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

[0605] Suspensions, each containing 50 mg of medicament per 5.0 ml doseare made as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthangum  4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mgMicrocrystalline cellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mgFlavor and Color q.v. Purified water to  5.0 ml

[0606] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

FORMULATION EXAMPLE 8

[0607] Quantity Ingredient (mg/capsule) Active Ingredient  15.0 mgStarch 407.0 mg Magnesium stearate  3.0 mg Total 425.0 mg

[0608] The active ingredient, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 560 mg quantities.

FORMULATION EXAMPLE 9

[0609] A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg corn oil   1 ml

FORMULATION EXAMPLE 10

[0610] A topical formulation may be prepared as follows: IngredientQuantity Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin20 g White Soft Paraffin to 100 g

[0611] The white soft paraffin is heated until molten. The liquidparaffin and emulsifying wax are incorporated and stirred untildissolved. The active ingredient is added and stirring is continueduntil dispersed. The mixture is then cooled until solid.

[0612] Another preferred formulation employed in the methods of thepresent invention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

[0613] Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

[0614] Indirect techniques, which are generally preferred, usuallyinvolve formulating the compositions to provide for drug latentiation bythe conversion of hydrophilic drugs into lipid-soluble drugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

[0615] Other suitable formulations for use in the present invention canbe found in Remington's Pharmaceutical Sciences, Mace PublishingCompany, Philadelphia, Pa., 17th ed. (1985).

[0616] Utility

[0617] The compounds and pharmaceutical compositions of the inventionare useful in inhibiting β-amyloid peptide release and/or its synthesis,and, accordingly, have utility in treating Alzheimer's disease inmammals including humans.

[0618] As noted above, the compounds described herein are suitable foruse in a variety of drug delivery systems described above. Additionally,in order to enhance the in vivo serum half-life of the administeredcompound, the compounds may be encapsulated, introduced into the lumenof liposomes, prepared as a colloid, or other conventional techniquesmay be employed which provide an extended serum half-life of thecompounds. A variety of methods are available for preparing liposomes,as described in, e.g., Szoka, et al., U.S. Pat. Nos. 4,235,871,4,501,728 and 4,837,028 each of which is incorporated herein byreference.

[0619] The amount of compound administered to the patient will varydepending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions are administered to a patient alreadysuffering from AD in an amount sufficient to at least partially arrestfurther onset of the symptoms of the disease and its complications. Anamount adequate to accomplish this is defined as “therapeuticallyeffective dose.” Amounts effective for this use will depend on thejudgment of the attending clinician depending upon factors such as thedegree or severity of AD in the patient, the age, weight and generalcondition of the patient, and the like. Preferably, for use astherapeutics, the compounds described herein are administered at dosagesranging from about 1 to about 500 mg/kglday.

[0620] In prophylactic applications, compositions are administered to apatient at risk of developing AD (determined for example by geneticscreening or familial trait) in an amount sufficient to inhibit theonset of symptoms of the disease. An amount adequate to accomplish thisis defined as “prophylactically effective dose.” Amounts effective forthis use will depend on the judgment of the attending cliniciandepending upon factors such as the age, weight and general condition ofthe patient, and the like. Preferably, for use as prophylactics, thecompounds described herein are administered at dosages ranging fromabout 1 to about 500 mg/kg/day.

[0621] As noted above, the compounds administered to a patient are inthe form of pharmaceutical compositions described above. Thesecompositions may be sterilized by conventional sterilization techniques,or may be sterile filtered. The resulting aqueous solutions may bepackaged for use as is, or lyophilized, the lyophilized preparationbeing combined with a sterile aqueous carrier prior to administration.The pH of the compound preparations typically will be between 3 and 11,more preferably from 5 to 9 and most preferably from 7 and 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of pharmaceutical salts.

[0622] The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

[0623] In the examples below, the following abbreviations have thefollowing meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning.

[0624] BOC=tert-butoxycarbonyl

[0625] BOP=benzotriazol- 1 -yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate

[0626] bd=broad doublet

[0627] bs=broad singlet

[0628] c=concentration (g/mL)

[0629] CDI=1,1′-carbonyldiimidazole

[0630] d=doublet

[0631] dd=doublet of doublets

[0632] DCM=dichloromethane

[0633] DEAD=diethyl azodicarboxylate

[0634] DMF=dimethylformamide

[0635] DMSO=dimethylsulfoxide

[0636] EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

[0637] EEDQ=2-ethoxy- 1-ethoxycarbonyl- 1,2-dihydroquinoline

[0638] eq.=equivalents

[0639] EtOAc=ethyl acetate

[0640] EtOH=ethanol

[0641] g=grams

[0642] L=liter

[0643] m=multiplet

[0644] max=maximum

[0645] MeOH=methanol

[0646] meq=milliequivalent

[0647] mg=milligram

[0648] mL=milliliter

[0649] mm=millimeter

[0650] mmol=millimole

[0651] N/A=not available

[0652] N=normal

[0653] ng=nanogram

[0654] nm=nanometers

[0655] OD=optical density

[0656] φ=phenyl

[0657] PEPC=1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide

[0658] psi=pounds per square inch

[0659] q=quartet

[0660] quint.=quintet

[0661] rpm=rotations per minute

[0662] s=singlet

[0663] t=triplet

[0664] TFA=trifluoroacetic acid

[0665] THF=tetrahydrofuran

[0666] tlc=thin layer chromatography

[0667] μL=microliter

[0668] UV=ultraviolet

[0669] In the examples below, all temperatures are in degrees Celcius(unless otherwise indicated) and each of the compounds set forth inthese examples was prepared by one of the following general procedures,unless otherwise indicated.

[0670] Additionally, the term “Aldrich” indicates that the compound orreagent used in the following procedures is commercially available fromAldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee,Wis. 53233 USA; the term “Fluka” indicates that the compound or reagentis commercially available from Fluka Chemical Corp., 980 South 2ndStreet, Ronkonkoma N.Y. 11779 USA; the term “Lancaster” indicates thatthe compound or reagent is commercially available from LancasterSynthesis, Inc., P.O. Box 100 Windham, N.H. 03087 USA; the term “Sigma”indicates that the compound or reagent is commercially available fromSigma, P.O. Box 14508, St. Louis Mo. 63178 USA; the term “Chemservice”indicates that the compound or reagent is commercially available fromChemservice Inc., Westchester, Pa.; the term “Bachem” indicates that thecompound or reagent is commercially available from Bachem BiosciencesInc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia,Pa. 19406 USA; the term “Maybridge” indicates that the compound orreagent is commercially available from Maybridge Chemical Co.Trevillett, Tintagel, Cornwall PL34 OHW United Kingdom; and the term“TCI” indicates that the compound or reagent is commercially availablefrom TCI America, 9211 North Harborgate Street, Portland Oreg. 97203;the term “Alfa” indicates that the compound or reagent is commerciallyavailable from Johnson Matthey Catalog Company, Inc. 30 Bond Street,Ward Hill, Mass. 01835-0747; the term “Novabiochem” indicates that thecompound or reagent is commercially available fromCalbiochem-Novabiochem Corp. 10933 North Torrey Pines Road, P.O. Box12087, La Jolla Calif. 92039-2087; the term “Oakwood” indicates that thecompound or reagent is commercially available from Oakwood, Columbia,S.C.; the term “Advanced Chemtech” indicates that the compound orreagent is commercially available from Advanced Chemtech, Louisville,Ky.; and the term “Pfaltz & Bauer” indicates that the compound orreagent is commercially available from Pfaltz & Bauer, Waterbury, Conn.,USA.

[0671] The following General Procedures A′-P′ and Examples A1-A74illustrate the synthesis of N-(aryl/heteroarylacetyl)amino acid esterswhich can be hydrolyzed to provide for N-(aryl/heteroarylacetyl)aminoacid starting materials of this invention. OtherN-(aryl/heteroarylacetyl)amino acid esters can be prepared using theseprocedures from commerically available or known starting materials.

GENERAL PROCEDURE A′ Coupling of R¹C(X′)(X″)C(O)Cl with H₂NCH(R²)C(O)XR³

[0672] To a stirred solution of (D,L)-alanine iso-butyl esterhydrochloride (from Example B below) (4.6 mmol) in 5 mL of pyridine wasadded 4.6 mmol of an acid chloride. Precipitation occurred immediately.The mixture was stirred for 3.5 h, diluted with 100 mL of diethyl ether,washed with 10% HCl three times, brine once, 20% potassium carbonateonce and brine once. The solution was dried over magnesium sulfate,filtered, and evaporated at reduced pressure to yield the product. Otheramino acid esters may also be employed in this procedure.

GENERAL PROCEDURE B′ Coupling of R¹C(X′)(X″)C(O)OH with H₂NCH(R²C(O)XR³

[0673] A solution of the acid (3.3 mmol) and CDI in 20 mL THF wasstirred for 2 h. L-alanine iso-butyl ester hydrochloride (from Example Bbelow) (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) oftriethylamine. The reaction mixture was stirred overnight. The reactionmixture was diluted with 100 mL of diethyl ether, washed with 10% HClthree times, brine once, 20% potassium carbonate once and brine once.The solution was dried over magnesium sulfate, filtered, and evaporatedat reduced pressure to yield the product. Other amino acid esters mayalso be employed in this procedure.

GENERAL PROCEDURE C′ Esterification of R¹C(X′)(X″)C(O)NHCH(R²)C(O)OHWith HOR³

[0674] To a stirred solution of phenylacetylvaline (1.6470 g, 7.0 mmol)in 20 mL THF was added CDI (1.05 g, 6.5 mmol) and the mixture wasstirred for 1.5 h. 2-Methylbutanol (0.53 g, 6 mmol) was added themixture, followed by addition of NaH (0.16 g, 6.5 mmol). Bubblingoccurred immediately. The reaction mixture was stirred overnight. Thereaction mixture was diluted with 100 mL of diethyl ether, washed with10% HCl three times, brine once, 20% potassium carbonate once and brineonce. The solution was dried over magnesium sulfate, filtered, andevaporated at reduced pressure to yield the product. Other N-acyl aminoacids and alcohols may also be employed in this procedure.

GENERAL PROCEDURE D′ Ester Hydrolysis to the Free Acid

[0675] Ester hydrolysis to the free acid was conducted by conventionalmethods. Below are two examples of such conventional de-esterificationmethods.

[0676] To the ester in a 1:1 mixture of CH₃OH/H₂O was added 2-5equivalents of K₂CO₃. The mixture was heated to about 50° C. for about0.5 to 1.5 hours until tlc showed complete reaction. The reaction wascooled to room temperature and the methanol was removed at reducedpressure. The pH of the remaining aqueous solution was adjusted to about2, and ethyl acetate was added to extract the product. The organic phasewas then washed with saturated aqueous NaCl and dried over MgSO₄. Thesolution was stripped free of solvent at reduced pressure to yield theproduct.

[0677] The amino acid ester was dissolved in dioxane/water (4. 1) towhich was added LiOH (˜2 eq.) that was dissolved in water such that thetotal solvent after addition was about 2:1 dioxane:water. The reactionmixture was stirred until reaction completion and the dioxane wasremoved under reduced pressure. The residue was diluted with EtOAc, thelayers were separated and the aqueous layer acidified to pH 2. Theaqueous layer was back extracted with EtOAc, the combined organics weredried over Na₂SO₄ and the solvent was removed under reduced pressureafter filtration. The residue was purified by conventional methods(e.g., recrystallization).

[0678] The following exemplifies this later example. The methyl ester of3-NO₂ phenylacetyl alanine 9.27 g (0.0348 mols) was dissolved in 60 mLdioxane and 15 mL of H₂O and adding LiOH (3.06 g, 0.0731 mol) that hasbeen dissolved in 15 mL of H₂O. After stirring for 4 hours, the dioxanewas removed under reduced pressure and the residue diluted with EtOAc,the layers were separated and the aqueous layer acidified to pH 2. Theaqueous layer was back extracted with EtOAc (4×100 mL), the combinedorganics were dried over Na₂SO₄ and the solvent was removed underreduced pressure after filtration. The residue was recrystallized fromEtOAc/isooctane giving 7.5 g (85%) of 3-nitrophenylacetyl alanine.C₁₁H₁₂N₂O₅ requires C=52.38, H=4.80, and N=11.11. Analysis found C=52.54, H =4.85, and N =11.08. [ce23=−29.9@589 nm.

GENERAL PROCEDURE E′ Low Temperature BOP Coupling of Acid and Alcohol

[0679] A solution of methylene chloride containing the carboxylic acid(100M %) and N-methyl morpholine (150 M %) was cooled to −20° C. undernitrogen. BOP (105 M %) was added in one portion and the reactionmixture was maintained at −20° C. for 15 minutes. The correspondingalcohol (120 M %) was added and the reaction mixture was allowed to warmto room temperature and stirred for 12 hours. The reaction mixture wasthen poured into water and extracted with ethyl acetate (3×). Thecombined ethyl acetate portions were backwashed with saturated aqueouscitric acid (2×), saturated aqueous sodium bicarbonate (2×), brine (1×),dried over anhydrous magnesium sulfate or sodium sulfate and the solventremoved under reduced pressure to yield the crude product.

GENERAL PROCEDURE F′ EDC Coupling of Acid and Amine

[0680] The acid derivative was dissolved in methylene chloride. Theamine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazolemonohydrate (1.2 eq.) were added in sequence. The reaction was cooled toabout 0° C. and then 1.2 eq. of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added.The solution was allowed to stir overnight and come to room temperatureunder N, pressure. The reaction mix was worked up by washing thesolution with saturated, aqueous Na₂CO₃, 0.1M citric acid, and brinebefore drying with Na₂SO₄ and removal of solvents to yield crudeproduct. Pure products were obtained by flash chromatography in anappropriate solvent.

GENERAL PROCEDURE G′ EDC Coupling of Acid and Amine

[0681] A round bottom flask was charged with carboxylic acid (1.0 eq.),hydroxybenzotriazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF undernitrogen atmosphere. An appropriate amount (1. 1 eq. for free amines and2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base wasadded to the well stirred mixture followed by EDC (1.1 eq.). Afterstirring from 4 to 17 hours at room temperature the solvent was removedat reduced pressure, the residue taken up in EtOAc (or similarsolvent)/water. The organic layer was washed with saturated aqueoussodium bicarbonate solution, 1N HCl, brine and dried over anhydroussodium sulfate. In some cases, the isolated product was analyticallypure at this stage while, in other cases, purification viachromatography and/or recrystallization was required prior to biologicalevaluation.

GENERAL PROCEDURE H′ Coupling of R¹C(X′)(X″)C(O)Cl with H₂NCH(R²)C(O)XR³

[0682] An excess of oxalyl chloride in dichloromethane was added to theacid derivative together with one drop of DMF. The resulting mixture wasstirred for about 2 hours or until bubbling ceases. The solvent was thenremoved under reduced pressure and rediluted with dry methylenechloride. To the resulting solution was added about 1.1 eq. of theappropriate amino acid ester and triethylamine (1.1 eq. in methylenechloride). The system was stirred at room temperature for 2 hours andthen the solvent was removed under reduced pressure. The residue wasdissolved in ethyl acetate, washed with 1N HCl followed by 1N NaOH. Theorganic layer was dried over anhydrous soldium sulfate, filtered and thesolvent removed under reduced pressure to provide for the desiredproduct.

GENERAL PROCEDURE I′ P-EPC Coupling

[0683] P-EPC coupling employs an amino acid ester and a substitutedacetic acid compound. The acetic acid derivative is well known in theart and is typically commercially available. The amino acid ester isprepared by conventional methods from the known and typicallycommercially available N-BOC amino acid as described in GENERALPROCEDURE J′ below.

[0684] Specifically, the appropriate amino ester free base (0.0346mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in2.0 mrL CHCl₃ (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g)and the reaction was mixed for 4 days at 23° C. The reaction wasfiltered through a plug of cotton, rinsed with 2.0 mL of CHCl₃ and thefiltrate evaporated under a stream of nitrogen. The purity of eachsample was determined by ¹H NMR and ranged from 50% to >95%. Between 8.0and 15.0 mg of final product was obtained from each reaction and wastested without additional purification.

GENERAL PROCEDURE J′ Synthesis of Amino Acid Esters From theCorresponding N-BOC Amino Acid

[0685] A. Esterification of the Acid.

[0686] The N-BOC amino acid was dissolved in dioxane and treated with anexcess of alcohol (-1.5 eq.) and catalytic DMAP (100 mg) at 0° C.Stirring was continued until reaction completion whereupon the productwas recovered by conventional methods.

[0687] B. Removal of N-BOC Group.

[0688] The N-BOC protected amino acid was dissolved in methylenechloride (0.05M) and treated with 10 eq. of TFA at room temperatureunder a nitrogen atmosphere. The reaction was monitored by tlc untilstarting material was consumed usually within 1-5 hours. An additional10 eq. of TFA was added to the reaction if the starting material wasstill present after 5 hours. The reaction was carefully neutralized withNa₂CO₃, separated, the organic layer washed with brine and dried overanhydrous Na₂SO₄. The crude amine was then used without purification.

[0689] Specific exemplification of these procedures are as follows:

[0690] 1. Racemic (±)-N-BOC-α-amino butyric acid (Aldrich) (9.29 g,0.0457 mol) was dissolved in 100 mL of dioxane and treated withiso-butyl alcohol (6.26 mL, 0.0686 mol), EDC (8.72 g, 0.0457) andcatalytic DMAP (100 mg) at 0C. After stirring for 17 hours, the organicswere evaporated at reduced pressure, the residue diluted with EtOAcwashed with NaHCO₃, brine and dried over Na₂SO₄. Evaporation yields 8.42g (71%) of an oil. C₁₃H₂₅NO₄ requires: C=60.21, H=9.72, and N=5.40. Analfound: C=59.91, H=9.89, and N=5.67.

[0691] The above N-BOC amino acid ester (8.00 g, 0.032 mol) wasdeprotected as above giving 3.12 g (61 %) of the free base as acolorless oil which solidifies upon standing.

[0692] 2. L-N-BOC-alanine (Aldrich) (8.97 g, 0.047 mol) was dissolved in100 mL of CH₂Cl₂, iso-butyl alcohol (21.9 mL, 0.238 mol) and treatedwith DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at 0° C. The mixture wasstirred for 17 hours, diluted with H₂O, washed with 1.0 N HCl, NaHCO₃,then brine and the organics were dried over Na₂SO₄. Filtration andevaporation yields 11.8 g (quantitative) of L-N-BOC alanine iso-butylester which is contaminated with a small amount of solvent. A sample wasvacuum dried for analytical analysis. C₁₂H₂₃NO₄ requires: C=58.79,H=9.38, and N=5.71. Anal found: C=58.73, H=9.55, and N=5.96.

[0693] The above N-BOC amino acid ester (11.8 g, 0.0481 mol) wasdeprotected as above. The free base was converted to the correspondingHCl salt using saturated HCl (g)/EtOAc to give L-N-alanine iso-butylester hydrochloride. Obtained 4.2 g (48%) of a colorless solid.C₇H₁₅NO₂. HCl requires: C=46.28, H=8.88, and N=7.71. Anal found:C=46.01, H=8.85, and N=7.68.

GENERAL PROCEDURE K′

[0694] Methyl ester formation from amino acids The amino acid (aminoacid or amino acid hydrochloride) is suspended in methanol and chilledto 0° C. HCl gas is bubbled through this solution for 5 minutes. Thereaction is allowed to warm to room temperature then stirred for 4hours. The solvents are then removed at reduced pressure to afford thedesired amino acid methyl ester hydrochloride. This product is usuallyused without further purification.

Example A′ Synthesis of free and polymer bound PEPC

[0695] N-ethyl-N′-3-( 12pyrrolidinyl)propylurea

[0696] To a solution of 27.7 g (0.39 mol) ethyl isocyanate in 250 mLchloroform was added 50 g (0.39 mol) 3-(1-pyrrolidinyl)propylaminedropwise with cooling. Once the addition was complete, the cooling bathwas removed and the reaction mixture stirred at room temperature for 4hours. The reaction mixture was then concentrated under reduced pressureto give 74.5 g (96.4%) of the desired urea as a clear oil.

[0697] 1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide (P-EPC)

[0698] To a solution of 31.0 g (0.156 mol)N-ethyl-N′-3-(l-pyrrolidinyl)propylurea in 500 mL dichloromethane wasadded 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0°C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonylchloride in 400 mL dichloromethane dropwise at such a rate as tomaintain the reaction at 0-5° C. After the addition was complete, thereaction mixture was warmed to room temperature and then heated toreflux for 4 hours. After cooling to room temperature, the reactionmixture was washed with saturated aqueous potassium carbonate (3×150mL). The aqueous phases were combined and extracted withdichloromethane. All organic phases were combined and concentrated underreduced pressure. The resultant orange slurry was suspended in 250 mLdiethyl ether and the solution decanted off from the solid. Theslurry/decantation process was repeated 3 more times. The ethersolutions were combined and concentrated under reduced pressure to give18.9 g (67%) of the desired product as a crude orange oil. A portion ofthe oil was distilled under vacuum to give a colorless oil distilling at78-82° C. (0.4 mm Hg).

[0699] Preparation of a Polymer Supported Form of1-(3-(1-pyrrolidinylpropyl)-3-ethylcarbodiimide (P-EPC)

[0700] A suspension of 8.75 g (48.3 mmol)l-(3-(l-pyrrolidin-yl)propyl)-3-ethylcarbodiimide and 24.17 g (24.17mmol) Merrifield's resin (2% cross-linked, 200-400 mesh,chloromethylated styrene/divinylbenzene copolymer, 1 meq. Cl/g) indimethylformamide was heated at 100° C for 2 days. The reaction wascooled and filtered and the resulting resin washed sequentially with 1 LDMF, 1 L THF and 1 L diethyl ether. The remaining resin was then driedunder vacuum for 18 hours.

Example B′ Preparation of Alanine iso-butyl Ester Hydrochloride

[0701] A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (orL-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and200 mL of isobutanol was refluxed for 1.5 hours and the volatiles wereremoved completely on a rotavapor of 90° C. under reduced pressure togive (D,L)-alanine iso-butyl ester hydrochloride (or L-alanine iso-butylester hydrochloride), which was pure enough to be used for furthertransformations.

Example C′ Preparation of 3,5-Dichlorophenylacetic Acid

[0702] To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in75 mL of dichloromethane at 0° C. was added 1.8 mL of methanesulfonylchloride followed by 3.5 mL of triethylamine added dropwise.After 2 hours the solution was diluted to 150 mL with dichloromethane,washed with 3N HCl, saturated aqueous NaHCO₃ dried with Na₂SO₄ and thesolvents removed to yield the desired 3,5-dichlorobenzylmethanesulfonate as a yellow oil that was used without purification.

[0703] The crude sulfonate was dissolved in 50 mL of DMF at 0° C. andthen 3 g of KCN was added. After 2 hours an additional 50 mL of DMF wasadded and the solution was stirred for 16 hours. The red solution wasdiluted with 1 L of H₂O and acidified to pH 3 with 3N HCl. The aqueoussolution was extracted with dichloromethane. The combined organics werewashed with 3N HCl, dried with Na₂SO₄ and the solvents removed atreduced pressure to yield crude 3,5-dichlorophenylacetonitrile which wasused without purification.

[0704] The nitrile was added to a mixture of 40 mL of concentratedsulfuric acid and 50 mL H₂O and heated to reflux for 48 hours, cooled toroom temperature and stirred for 48 hours. The reaction was diluted into1 L of crushed ice, warmed to toom temperature and extracted with 2×200mL of dichloromethane and 2×200 mL of ethylacetate. Both sets oforganics were combined and washed with saturated aqueous NaHCO₃. TheNaHCO₃ fractions were combined and acidified to pH 1 with 3N HCl. Thewhite solid was too fine to filter and was extracted out with 2×200 mLof dichloromethane. The combined organics were dried with Na₂SO₄ and thesolvents removed at reduced presure to yield crude3,5-dichlorophenylacetic acid as a white solid. The solid was slurriedwith hexane and filtered to get 1.75g of white solid.

[0705] NMR (CDCl₃): (in ppm) 3.61 (s, 2H), 7.19 (s,1H), 7.30 (s, 1H)

Example D′ Synthesis of N-(3-Chlorophenylacetyl)Alanine

[0706] The title compound was prepared using L-alanine (Nova Biochem)and 3-chlorophenyl acetic acid (Aldrich) by following General ProceduresF′ or G′, followed by hydrolysis using General Procedure D′.

[0707] Example A1

Synthesis of N-(phenylacetyl)-D,L-alanine iso-butyl Ester

[0708] Following General Procedure A′ above and using phenylacetylchloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (fromExample B′ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt2O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[0709] NMR data was as follows:

[0710]¹H-nmr (CDCl₃): δ=7.23-7.36 (m, 5H), 6.18 (d, 1H), 4.58 (t, J=7.3Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90 (m, IH), 1.34 (d, J=7.2 Hz,3H), 0.89 (d, J=6.8 Hz, 6H).

[0711]¹³C-nmr (CDCl₃): δ=172.7, 170.3, 134.5, 129.2, 128.8, 127.2, 71.3,48.1, 43.4, 27.5, 18.8, 18.3.

[0712] C₁₅H₂₁NO₃ (MW=263.34; Mass Spectroscopy (MH⁺=264))

Example A2 Synthesis of N-(3-Phenylpropionyl)-D,L-alanine iso-butylEster

[0713] Following General Procedure A′ above and using 3-phenylpropionylchloride (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (fromExample B′ above), the title compound was prepared as a solid having amelting point of from 51°-54 ° C. The reaction was monitored by tlc onsilica gel and purification was by extraction with Et₂O followed bywashes with aqueous K₂CO₃ and aqueous HCl.

[0714] NMR data was as follows:

[0715]¹H-nmr (CDCl₃): δ=7.25 (m, 2H), 7.19 (m, 3H), 6.28 (d, J=7.2 Hz,1H), 4.58 (quint., J=7.2 Hz, 1H), 3.89 (m, 2H), 2.95 (t, J=7.7 Hz, 2H),2.50 (mn, 2H), 1.92 (m, 1H), 1.33 (d, J=7.1 Hz, 3H), 0.91 (d, J=6.7 Hz,6H).

[0716]¹³C-nmr (CDCl₃): δ=173.0, 171.5, 140.6, 128.3, 128.1, 126.0, 71.2,47.8, 37.9, 31.4, 27.5, 18.79, 18.77, 18.3.

[0717] C₁₆H₂₃NO₃ (MW=277.37, Mass Spectroscopy (MH⁺278))

Example A3 Synthesis of N-(3-Methylpentanoyl)-L-alanine iso-butyl Ester

[0718] Following General Procedure B′ and using 3-methylpentanoic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′above), the title compound was prepared as an oil. The reaction wasmonitored by tic on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃and aqueous HCl.

[0719] NMR data was as follows:

[0720]¹H-nmr (CDCl₃): δ=6.08 (d, J 5.9 Hz, 1H), 4.62 (quint., J=7.3 Hz,1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84-2.00 (m, 3H), 1.40 (d, J=7.2 Hz,3H), 1.35 (m, 1H), 1.20 (m, 1H), 0.85-0.96 (m, 12H).

[0721]¹³C-nmr (CDCl₃): δ=173.3, 172.1, 71.4, 47.9, 43.9, 32.3, 29.38,29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3.

[0722] C₁₃H₂₅NO₃ (MW=243.35, Mass Spectroscopy (MH⁺244))

Example A4 Synthesis of N-[(4-Chlorophenyl)Acetyl]-L-alanine iso-butylEster

[0723] Following General Procedure B′ and using 4-chlorophenylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleB′ above), the title compound was prepared as a solid having a meltingpoint of 111° -113° C. The reaction was monitored by tlc on silica geland purification was by extraction with Et₂O followed by washes withaqueous K₂CO₃ and aqueous HCl.

[0724] NMR data was as follows:

[0725]¹H-nmr (CDCl₃): δ=7.30 (d, J=8.2 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H),6.18 (d, J=5.5 Hz, 1H), 4.57 (quint., J=7.2 Hz, 1H), 3.88 (m, 2H), 3.53(s, 2H), 1.91 (m, 1H), 1.36 (d, J=7.1 Hz, 3H), 0.90 (d, J=6.8 Hz, 6H).

[0726]¹³C-nmr (CDCl₃): δ=172.8, 169.8, 133.1, 133.0, 130.6, 128.9, 71.4,48.2, 42.6, 27.6, 18.85, 18.82, 18.4.

[0727] C₁₅H₂₀NO₃Cl (MW=297.78, Mass Spectroscopy (MH⁺298))

Example A5 Synthesis of N-[(3,4dichlorophenyl)acetyl]-L-alanineiso-butyl ester

[0728] Following General Procedure B′ and using 3,4dichlorophenylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleB′ above), the title compound was prepared as a solid having a meltingpoint of 81°-83° C. The reaction was monitored by tlc on silica gel andpurification was by extraction with Et₂O followed by washes with aqueousK₂CO₃ and aqueous HCl.

[0729] NMR data was as follows:

[0730]¹H-nmr (CDCl₃): δ=0.90 (d, J=6.8 Hz, 6H), 1.38 (d, J=7.1 Hz, 3H),1.91 (m, 1H), 3.50 (s, 2H), 3.90 (m, 2H), 4.57 (quint., J=7.1 Hz, 1H),6.31 (d, J=4.9 Hz, 1H),7.12 (m, 1H), 7.38 (m, 2H).

[0731]¹³C-nmr (CDCl₃): δ=18.4, 18.8, 18.9, 27.6, 42.2, 48.3, 71.5,128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2, 172.8.

[0732] C₁₅H₁₉NO₃Cl₂ (MW=332.23, Mass Spectroscopy (MH⁺332))

Example A6 Synthesis of N-[(4methylphenyl)acetyl]-D,L-alanine iso-butylester

[0733] Following General Procedure B′ and using 4-methylphenylaceticacid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (fromExample B′ above), the title compound was prepared as a solid having amelting point of 102°-104° C. The reaction was monitored by tlc onsilica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification was byextraction with Et₂O followed by washes with aqueous K₂CO₃ and aqueousHCl.

[0734] NMR data was as follows:

[0735]¹H-nmr (CDCl₃): δ=0.90 (d, J=6.7 Hz, 6H), 1.35 (d, J=7.2 Hz, 3H),1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H), 4.58 (m, 1H),6.05 (bd, 1H), 7.16 (s, 4H).

[0736]¹³C-nmr (CDCl₃): δ=18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1,71.3, 129.2, 129.6, 131.3, 136.9, 170.6, 172.8.

[0737] C₁₆H₂₃NO₃ (MW=277.37, Mass Spectroscopy (MH⁺278))

Example A7 Synthesis of N-[(3pyridyl)acetyl]-D,L-alanine iso-butyl ester

[0738] Following General Procedure F′ and using 3-pyridylacetic acidhydrochloride (Aldrich) and D,L-alanine isobutyl ester hydrochloride(from Example B′ above), the title compound was prepared as a solidhaving a melting point of 62°-64° C. The reaction was monitored by tlcon silica gel (Rf=0.48 10% methanol/dichloromethane) and purificationwas by silica gel chromatography.

[0739] NMR data was as follows:

[0740]¹H-nmr (CDCl₃): δ=8.40 (d, J 2.8, 2H); 7.6 (m, 1H): 7.16 (m, 2H);4.5 (quint., J=7.2, 7.2, 1H); 3.8 (m, 2H); 3.48 (s, 2H); 1.8 (m, 1H);1.30 (d, J 7.2, 3H); 0.81 (d, J=6.7, 6H).

[0741]¹³C-nmr (CDCl₃): δ=173.4, 170.1, 150.6, 148.8, 137.4, 131.4,124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6.

[0742] C₁₄H₂₀N₂O₃ (MW=264, Mass Spectroscopy (MH⁺265))

Example A8 Synthesis of N-[(1-naphthyl)acetyl]-L]alanine iso-butyl ester

[0743] Following General Procedure B′ and using 1-naphthylacetic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′above), the title compound was prepared as a solid having a meltingpoint of 69°-73° C. The reaction was monitored by tlc on silica gel andpurification was by extraction with Et₂O followed by washes with aqueousK₂CO₃ and aqueous HCl.

[0744] NMR data was as follows:

[0745]¹H-nmr (CDCl₃): δ=0.83 (m, 6H), 1.25 (d, J=7.1 Hz, 3H), 1.81 (m,1H), 3.79 (m, 2H), 4.04 (2s, 2H), 4.57 (quint., J=7.3 Hz, 1H), 5.99 (d,J 7.1 Hz, 1H), 7.44 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7.98 (m, 1H).

[0746]¹³C-nmr (CDCl₃): δ=18.2, 18.81, 18.83, 27.5, 41.5, 48.2, 71.3,123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7, 130.7, 132.0, 133.9,170.3, 172.5.

[0747] C₁₉H23NO₃ (MW=313.40, Mass Spectroscopy (MH⁺314))

Example A9 Synthesis of N-[(2-naphthyl)acetyl]-L-alanine iso-butyl ester

[0748] Following General Procedure B′ and using 2-naphthylacetic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′above), the title compound was prepared as a solid having a meltingpoint of 128°-129° C. The reaction was monitored by tlc on silica geland purification was by extraction with Et₂O followed by washes withaqueous K₂CO₃ and aqueous HCl. NMR data was as follows:

[0749]¹H-nmr (CDCl₃): δ=0.86 (m, 6H), 1.35 (d, J=7.1 Hz, 3H), 1.78 (m,1H), 3.76 (s, 2H), 3.87 (m, 2H), 4.62 (quint., J=7.2 Hz, 1H), 6.13 (d,J=7.1 Hz, 1H), 7.41 (m, 1H), 7.48 (m, 2H), 7.74 (s, 1H), 7.83 (m, 3H).

[0750]³C-nmr (CDCl₃): δ=18.4, 18.82, 18.85, 27.6, 43.7, 48.2, 71.4,125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7, 132.0, 132.5, 133.5,170.3, 172.8.

[0751] C₁₉H₂₃NO₃ (MW=313.40, Mass Spectroscopy (MH⁺314)).

Example A10 Synthesis of N-(4phenylbutanoyl)-L-alanine iso-butyl ester

[0752] Following General Procedure B′ and using 4-phenylbutanoic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′above), the title compound was prepared as an oil. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[0753] NMR data was as follows:

[0754]¹H-nmr (CDCl₃): δ=0.92 (d, J=6.7 Hz, 6H), 1.38 (d, J=7.1 Hz, 3H),1.96 (m, 3H), 2.21 (t, J=7.1 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 3.90 (m,2H), 4.59 (quint., J=7.2 Hz, 1H), 6.31 (d, 1H), 7.16 (m, 3H), 7.24 (m,2H).

[0755]¹³C-nmr (CDCl₃): δ=18.3, 18.75, 18.78, 26.8, 27.5, 34.9, 35.3,47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0.

[0756] C₁₇H₂₅NO₃ (MW=291.39, Mass Spectroscopy (MH⁺292)).

Example A11 Synthesis of N-(5-phenylpentanoyl)-L-alanine iso-butyl ester

[0757] Following General Procedure B′ and using 5-phenylpentanoic acid(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′above), the title compound was prepared as an oil. The reaction wasmonitored by tlc on silica gel and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[0758] NMR data was as follows:

[0759]¹H-nmr (CDCl₃): δ=7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 4.59(quint., J=7.3 Hz, 1H), 3.91 (m, 2H), 2.61 (t, J=7.2 Hz, 2H), 2.22 (t,J=7.2 Hz, 2H), 1.93 (m, 1H), 1.66 (m, 4H), 1.38 (d, J=7.2 Hz, 3H), 0.92(d, J=6.7 Hz, 6H).

[0760]¹³C-nmr (CDCl₃): δ=173.1, 172.3, 142.0, 128.2, 128.1, 125.6, 71.2,47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80, 18.77, 18.4.

[0761] C₁₈H₂₇NO₃ (MW=305.39, Mass Spectroscopy (MH⁺306)).

Example A12 Synthesis of N-[(4pyridyl)acetyl]-D,L-alanine iso-butylester

[0762] Following General Procedure F′ and using 4-pyridylacetic acidhydrochloride (Aldrich) and (D,L)-alanine iso-butyl ester hydrochloride(from Example B′ above), the title compound was prepared as a solidhaving a melting point of 64°-66° C. The reaction was monitored by tlcon silica gel (Rf=0.43 10% methanolldichloromethane) and purificationwas by silica gel chromatography.

[0763] NMR data was as follows:

[0764]¹H-nmr (CDCl₃): δ=8.51 (dd, J=1.6, 2.8, 1.6, 2H); 7.23 (dd, J=4.3,1.6, 4.4, 2H); 6.71 (d, J=6.8, 1H); 4.56 (quint., J=7.3, 7.2, 1H); 3.88(m, 2H); 3.53 (s, 2H); 1.89 (m, 1H); 1.36 (d, J=7.2, 3H); 0.88 (d,J=6.7, 6H).

[0765]¹³C-nmr (CDCl₃): δ=173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9,43.0, 28.2, 19.5, 19.5, 18.9.

[0766] C₁₄H₂₀N₂O₃ (MW=264, Mass Spectroscopy (MH⁺265))

Example A13 Synthesis of N-(phenylacetyl)-L-alaninie iso-butyl ester

[0767] Following General Procedure B′ and using phenylacetyl chloride(Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′above), the title compound was prepared as a solid having a meltingpoint of 45°-47° C. The reaction was monitored by tlc on silica gel andpurification was by extraction with Et₂O followed by washes with aqueousK₂CO₃ and aqueous HCl.

[0768] NMR data was as follows:

[0769]¹H-nmr (CDCl₃): δ=7.24-7.39 (m, 5H), 6.14 (d, 1H), 4.58 (t, J=7.3Hz, 1H), 3.88 (m, 2H), 3.58 (s, 2H), 1.90 (m, 1H), 1.35 (d, J=7.2 Hz,3H), 0.89 (d, J=6.7 Hz, 6H).

[0770]¹³C-nmr (CDCl₃): δ=172.8, 170.4, 134.5, 129.3, 128.9, 127.2, 71.3,48.1, 43.5, 27.5, 18.9, 18.8, 18.4.

[0771] C₁₅H₂₁NO₃ (MW=263.34, Mass Spectroscopy (MH⁺264)).

Example A14 Synthesis of 2-[(3,4dichlorophenyl)acetamnido]butyric acidisobutyl ester

[0772] Following General Procedure I′ above and using3,4-dichlorbphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above) the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0773] NMR data was as follows:

[0774]¹H-nmr (CDCl₃): 6 7.36 (m, 3H), 6.03 (bd, 1H), 4.54 (m, 1H), 3.87(m, 2H), 3.49 (s, 2H), 1.93 (m, 2H), 1.72 (m, 1H), 0.88 (d, 6H), 0.80(t, 3H).

Example A 15 Synthesis of 2-[(3-methoxyphenyl)acetamido]butyric acidiso-butyl ester

[0775] Following General Procedure I′ above and using3-methoxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared frollowing General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0776] NMR data was as follows:

[0777]¹H-nmr (CDCl₃): δ=6.75 (m, 4H), 5.93 (bd, 1H), 4.51 (m, 1H), 3.83(m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1.82 (m, 2H), 1.60 (m, 1H), 0.84(d, 6H), 0.74 (t, 3H).

[0778] C₁₇H₂₅NO₄ (MW=307.39, Mass Spectroscopy (MH⁺309)).

Example A16 Synthesis of 2-[(4nitrophenyl)acetamido]butyric acidiso-butyl ester

[0779] Following General Procedure I′ above and using4-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0780] NMR data was as follows:

[0781]¹H-nmr (CDCl₃): δ=8.16 (d, 2H), 7.44 (d, 2H), 6.04 (bd, 1H), 4.55(m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.67 (m, 1H), 0.85(d, 6H), 0.81 (t, 3H).

[0782] C₁₆H₂₂N₂O₅ (MW=322.36, Mass Spectroscopy (MH⁺323)).

Example A17 Synthesis of 2-[(3,4methylenedioxyphenyl)acetamido]butyricacid iso-butyl ester

[0783] Following General Procedure I′ above and using3,4-(methylenedioxy)-phenyl acetic acid (Aldrich) and iso-butyl2-aminobutyrate (prepared following General Procedure J′ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[0784] NMR data was as follows:

[0785]¹H-nmr (CDCl₃): δ=6.72 (m, 3H), 5.92 (bd, 1H), 4.54 (m, 1H), 3.865 (m, 2H), 3.66 (s, 2H), 1.86 (m, 2H), 1.66 (m, 1H), 0.89 (d, 6H), 0.79(t, 3H).

Example A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butylester

[0786] Following General Procedure I′ above and using 3-thiopheneaceticacid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure J′ above), the title compound was prepared. The reaction wasmonitored by tic on silica gel and purification was by filtration asdescribed in the general procedure.

[0787] NMR data was as follows:

[0788]¹H-nmr (CDCl₃): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05(bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91(d, 6H), 0.86 (t, 3H).

Example A19 Synthesis of 2-[(4chlorophenyI)acetamido]butyric acidiso-butyl ester

[0789] Following General Procedure I′ above and using4-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0790] NMR data was as follows:

[0791]¹H-nmr (CDCl₃): δ=7.22 (m, 2H), 7.11 (m, 2H), 5.80 (m, 1H), 4.44(m, 1H), 3.78 (m, 2H), 3.43 (s, 2H), 1.77 (m, 2H), 1.56 (m, 1H), 0.83(d, 6H) 0.71 (t, 3H).

Example A20 Synthesis of 2-[(3-nitrophenyl)acetamido]butyric acidiso-butyl ester

[0792] Following General Procedure I′ above and using3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0793] NMR data was as follows:

[0794]¹H-nmr (CDCl₃): δ=8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46(m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (m, 1H), 0.98(d, 6H) 0.71 (t, 3H).

Example A21 Synthesis of 2-[(2-hydroxyphenyl)acetamido]butyric acidiso-butyl ester

[0795] Following General Procedure I′ above and using2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0796] NMR data was as follows: ¹H-nmr (CDCl₃): δ=7.14 (m, 1H), 7.01 (m,1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.46 (m, 1H), 4.51 (m, 1H), 3.87 (m,2H), 3.57 (s, 2H), 2.01 (m, 2H), 1.75 (m, 1H), 0.89 (d, 6H), 0.85 (t,3H).

Example A22 Synthesis of 2-[(2-naphthyl)acetadimo]butyric acid iso-butylester

[0797] Following General Procedure I′ above and using 2-naphthylaceticacid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure J′ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[0798] NMR data was as follows:

[0799]¹H-nmr (CDCI,): δ=7.83 (m, 7H), 5.95 (m, 1l), 4.58 (m, 1H), 3.84(m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63 (m, 1H), 0.91 (d, 6H), 0.81(t, 3H).

[0800] C₂₀H₂₅NO₃ (MW=327.42, Mass Spectroscopy (MH⁺328)).

Example A23 Synthesis of 2-[(2,4-dichlorophenyl)acetamido]butyric acidiso-butyl ester

[0801] Following General Procedure I′ above and using2,4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0802] NMR data was as follows:

[0803]¹H-nmr (CDCl₃): δ=7.49 (m, 1H), 7.22 (m, 2H) 5.98 (m, 1H), 4.52(m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H) 0.87 (d,6H), 0.80 (t, 3H).

Example A24 Synthesis of 2-[(4bromophenyl)acetamido]butyric acidiso-butyl ester

[0804] Following General Procedure I′ above and using4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0805] NMR data was as follows:

[0806]¹H-nmr (CDCl₃): δ=7.43 (d, 2H), 7.19 (d, 2H) 5.85 (m, 1H), 4.51(m, 1H), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m, 2H), 1.61 (m, 1H) 0.84 (d,6H), 0.76 (t, 3H).

[0807] C₁₆H₂₂NO₃Br (MW=356.26, Mass Spectroscopy (MH⁺358)).

Example A25 Synthesis of 2-[(3-chlorophenyl)acetamido])butyric acidiso-butyl ester

[0808] Following General Procedure I′ above and using3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0809] NMR data was as follows:

[0810]¹H-nmr (CDCl₃): δ=7.25 (m, 3H), 7.12 (m, 1H) 5.80 (m, 1H), 4.52(m, 1H)- 3.86 (m, 2H), 3.50 (s, 2H), 1.87 (m, 2H), 1.67 (m, 1H) 0.88 (d,6H), 0.77 (t, 3H).

[0811] C₁₆H₂₂NO₃Cl (MW=311.81 Mass Spectroscopy (MH⁺313)).

Example A26 Synthesis of 2-[(3-fluorophenyl)acetamido]butyric acidiso-butyl ester

[0812] Following General Procedure I′ above and using3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0813] NMR data was as follows:

[0814]¹H-nmr (CDCl₃): δ=7.31 (m, 1H), 7.01 (m, 3H) 5.95 (m, 1H), 4.54(m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (m, 2H), 1.65 (m, 1H) 0.87 (d,6H), 0.81 (t, 3H).

[0815] C₁₆H₂₂NO₃F (MW=295.35 Mass Spectroscopy (MH⁺296)).

Example A27 Synthesis of 2-[(benzothiazol-4-yl)acetarmido]butyric acidiso-butyl ester

[0816] Following General Procedure I′ above and using4-benzothiazol-4-yl acetic acid (Chemservice) and iso-butyl2-aminobutyrate (prepared following General Procedure J′ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[0817] NMR data was as follows:

[0818]¹H-nmr (CDCl₃): δ=7.82 (m, 1H), 7.51-7.21 (m, 4H) 5.84 (m, 1H),4.51 (m, 1H), 3.90 (s, 2H), 3.79 (m, 2H), 1.78 (m, 2H), 1.58 (m, 1H)0.80 (d, 6H), 0.66 (t, 3H).

Example A28 Synthesis of 2-[(2-methylphenyl)acetamido]butyric acidiso-butyl ester

[0819] Following General Procedure I′ above and using2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0820] NMR data was as follows:

[0821]¹H-nmr (CDCl₃): δ=7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85(m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H) 0.87 (d,6H), 0.77 (t, 3H).

[0822] C₁₇H₂₅NO₃ (MW=291.39 Mass Spectroscopy (M+291)).

Example A29 Synthesis of 2-[(2-fluorophenyl)acetamido]butyric acidiso-butyl ester

[0823] Following General Procedure I′ above and using2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0824] NMR data was as follows:

[0825]¹H-nmr (CDCl₃): δ=7.28 (m, 1H), 7.09 (m, 3H) 6.03 (m, 1H), 4.54(m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m, 2H), 1.64 (m, 1H) 0.88 (d,6H), 0.80 (t, 3H).

Example A30 Synthesis of 2-[(4fluorophenyl)acetarnido]butyric acidiso-butyl ester

[0826] Following General Procedure I′ above and using4-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure I′ above), the title compound wasprepared. The reaction was monitored by tdc on silica gel andpurification was by filtration as described in the general procedure.

[0827] NMR data was as follows:

[0828]¹H-nmr (CDCl₃): δ=7.20 (m, 2H), 6.97 (m, 2H) 5.87 (m, 1H), 4.492(m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1.86 (m, 2H), 1.60 (m, 1H) 0.87 (d,6H), 0.78 (t, 3H).

[0829] C₁₆H₂₂NO₃F (MW 295.35 Mass Spectroscopy (MH⁺296)).

Example A31 Synthesis of 2-[(3-bromophenyl)acetamido]butyric acidiso-butyl ester

[0830] Following General Procedure I′ above and using3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate(prepared following General Procedure above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0831] NMR data was as follows:

[0832]¹H-nmr (CDCl₃): δ=7.45 (m, 2H), 7.23 (m, 2H) 5.95 (m, 1H), 4.55(m, 1H) 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H), 1.68 (m, 1H) 0.91 (d,6H), 0.81 (t, 3H).

[0833] C₁₆H₂₂NO₃Br (MW=356.26 Mass Spectroscopy (M+357)).

Example A32 Synthesis of 2-[(3-trifluoromethylphenyl)acetamido]butyricacid iso-butyl ester

[0834] Following General Procedure I′ above and using3-trifluoromethylphenylacetic acid (Aldrich) and iso-butyl2-aminobutyrate (prepared following General Procedure J′ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[0835] NMR data was as follows:

[0836]¹H-nmr (CDCl₅): δ=7.52 (m, 1H), 7.47 (m, 2H) 6.01 (m, 1H), 4.56(m, 1H), 3.86 (m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H) 0.87 (d,6H), 0.80 (t, 3H).

[0837] C₁₇H22NO₃F₃ (MW=345.36 Mass Spectroscopy (MH⁺345)).

Example A33 Synthesis of 2-[(2-thienyl)acetamido]butyric acid iso-butylester

[0838] Following General Procedure I′ above and using 2-thiopheneaceticacid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure J′ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[0839] NMR data was as follows:

[0840]¹H-nmr (CDCl): 6 6.89 (m, 3H), 6.07 (bd, 1H), 4.50 (m, 1H), 3.82(m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62 (m, 1H), 0.81 (d, 6H), 0.75(t, 3H).

[0841] C₁₄H₂lNO₃S (MW=283.39, Mass Spectroscopy (MH⁺284)).

Example A34 Synthesis of 2-(phenylacetamido)butyric acid iso-butyl ester

[0842] Following General Procedure H′ above and using phenylacetic acid(Aldrich) and iso-butyl 2-aminobutyrate (prepared following GeneralProcedure J′ above), the title compound was prepared. The reaction wasmonitored by tic on silica gel and purification was by chromatography onsilica gel using 9:1 toluene:EtOAc as the eluant.

[0843] NMR data was as follows:

[0844]¹H-nmr (CDCl₃): δ=7.17-7.28 (m, 5H), 6.23 (bd, 1H), 4.51 (m, 1H),3.86 (m, 2H), 3.54 (s, 2H), 1.87 (m, 2H), 1.62 (m, 1H), 0.87 (d, 6H),0.78 (t, 3H).

[0845] C₁₆H₂₃NO₃ (MW=277.36, Mass Spectroscopy (MH⁺277)).

Example A35 Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester

[0846] Step A. Preparation of N-(phenylacetyl) valine

[0847] To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL(40 mmol) of phenylacetyl chloride (Aldrich). A colorless oilprecipitated. The reaction mixture was allowed to warm to roomtemperature and stirred for 18 hours, washed with 50 mL diethyl ether,acidified to pH 2-3 with aqueous HCl. The white precipitate formed wasfiltered off, washed thoroughly with water, followed by diethyl ether togive 7.1 g (30 mmol, 69% yield) of the title compound.

[0848] NMR data was as follows:

[0849]¹H-nmr (DMSO-d₆): δ=12.63 (s, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.27(m, 5H), 4.15 (m, 1H), 3.56 (d, J=13.8 Hz, 1H), 3.47 (d, J=13.8 Hz, 1H),2.05 (m, 1H), 0.87 (d, J=6.8, Hz, 3H), 0.84 (d, J=6.8 Hz, 3)

[0850]¹³C-nmr (DMSO-d₆): δ=173.2, 170.4, 136.6, 129.0, 128.2, 126.3,57.1, 41.9, 30.0, 19.2, 18.0

[0851] C₁₃H₁₇NO₃ (MW=235.29; Mass Spectroscopy (MH+=236))

[0852] Step B. Synthesis of N-(phenylacetyl)valine 2-methylbutyl ester

[0853] Following General Procedure C′ and using the N-(phenylacetyl)valine prepared in Step A above and 2-methylbutan-1-ol (Aldrich), thetitle compound was prepared as a diastereomeric mixture. The reactionwas monitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[0854] NMR data was as follows:

[0855]¹H-nmr (CDCl₃): δ=7.25-7.40 (m, 5H), 5.95 (d, 1H), 4.56 (m, 1H),3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m, 1H), 1.68 (m, 1H), 1.38 (m,1H), 1.15 (m 1H), 0.82-0.94 (m, 9H), 0.76 (d, 3H).

[0856]¹³C-nmr (CDCl₃): δ=171.84, 171.81, 170.7, 134.6, 129.31, 129.27,128.9, 127.3, 69.8, 57.0, 43.7, 33.9, 31.3, 25.9, 25.8,, 18.9, 17.4,16.34, 16.27, 11.12, 11.07.

[0857] C₁₈H₂₇NO₃ (MW=305.42, Mass Spectroscopy (MH 306)).

Example A36 Synthesis of N-(phenylacetyl)-Lmethionine iso-butyl ester

[0858] L-Methionine (0.129 g, 0.869 mmols) (Aldrich) was taken-up indioxane (5.0 mL) and treated with a saturated solution of sodiumbicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114mL, 0.822 mmols). After stirring for 17 hours at room temperature themixture was diluted with ethyl acetate, the layers separated and theaqueous layer acidified to pH 2 with 5N HCl. The crude product wasextracted into ethyl acetate, dried over sodium sulfate, vacuum driedand used without further purification.

[0859] N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolvedin 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC(0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g). After stirring for17 hours at 23° C, the mixture was evaporated at reduced pressure to anoil, the residue was diluted in EtOAc and washed with 0.1 N HCl andsaturated sodium bicarbonate. Chromatography on silica gel using 98:2CHCl₃/MeOH as eluant provided the pure product.

[0860] NMR data was as follows:

[0861]¹H-nmr (CDCl₃): δ=7.4-7.23 (m, 5H), 6.14 (bd, 1H), 4.70 (m, 1H),3.89 (d, 2H), 3.62 (s, 2H), 2.43 (m, 2H), 2.12 (m, 1H), 1.93 (m, 2H),0.94 (d, 6H).

[0862] C₁₇H₂₅NO₃S (MW=323.17, Mass Spectroscopy (M⁺323)

Example A37 Synthesis of N-(phenylacetyl)-L-leucine iso-butyl ester

[0863] L-Leucine (Aldrich) (0.114 g, 0.869 mmols) was taken-up indioxane (5.0 mL) and treated with a saturated solution of sodiumbicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114mL, 0.822 mmols). After stirring for 17 hours at room temperature themixture was diluted with ethyl acetate, the layers separated and theaqueous layer acidified to pH 2 with 5N HCl. The crude product wasextracted into ethyl acetate, dried over sodium sulfate, vacuum driedand used without further purification.

[0864] N-Phenylacetyl-L-leucine (0.0081 g, 0.038 mmol) was dissolved in2.0 MI, CHCl₃ (EtOH free) and iso-butyl alcohol (0.055 mL) and treatedwith P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for4 days, filtered through a plug of cotton and the filtrate evaporated atreduced pressure to an oil which was sufficiently pure for testing.

[0865] NMR data was as follows:

[0866] H-nmr (CDCl₃): δ=7.22 (m, 5H), 5.57 (d, 1H), 4.35 (m, 1H), 3.35(m, 3H), 1.35 (m, 4H), 0.68 (m, 9H).

[0867] C₁₈H₂₇NO₃ (MW=305.40, Mass Spectroscopy (M⁺305)).

Example A38 Synthesis of N-[(3-chlorophenyl)acetyl]alanine3-methylbut-2-enyl ester

[0868] Following General Procedure C′ above and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) and3-methylbut-2-en-1-ol (Aldrich), the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 30% EtOAc/hexane as the eluant.

[0869] NMR data was as follows:

[0870]¹H-nmr (CDCl₃): δ=7.39-7.16 (m, 4H), 6.06 (bd, 1H), 5.38-5.29 (m,1H), 4.63 (d, J=9Hz, 2H), 3.56 (s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39(d, J=9Hz, 3H).

Example A39 Synthesis of N-[(3-chlorophenyl)acetyl]alaninecyclopropylmethyl ester

[0871] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) andcyclopropylmethanol (Aldrich), the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[0872] NMR data was as follows:

[0873]¹H-nmr (CDCl₃): δ=7.2-7.1 (m, 4H), 6.09 (bs, 1H), 4.6 (dq, J=9 Hz,1H), 3.96 (dd, J=9Hz, 2H), 3.59 (s, 2H), 1.2 (d-, J=9Hz, 3H), 1.2-1.0(m, 1H), 0.603-0.503 (m, 2H), 0.300-0.203 (m, 2H).

Example A40 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-thienylmethyl ester

[0874] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) and2-thiophenemethanol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[0875] NMR data was as follows:

[0876]¹H-nmr (CDCl₃): δ=7.37-6.97 (m, 7H), 5.97 (q, J=14 Hz, 2H), 4.6(dq, J=9 Hz, 1H), 3.76 (s, 2H), 1.38 (d, J=9Hz, 3H).

Example A41 Synthesis of N-[(3-chlorophenyl)acetyl]alanine(1-methylcyclopropyl)methyl ester

[0877] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) and(1-methylcyclopropyl)methanol (Aldrich) the title compound can beprepared. The reaction was monitored by tlc on silica gel andpurification was by liquid chromatography using 3:7 EtOAc:hexane as theeluant.

[0878] NMR data was as follows:

[0879]¹H-nmr (CDCl₃): δ=8.6 (bd, J=9 Hz, 1H), 3.86 (q, J=14 Hz, 2H), 3.4(s, 2H), 2.29 (q, J=9 Hz, 1H), 1.3 (d, J=9Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H).

Example A42 Synthesis of N-[(3-chlorophenyl)acetyl]alanine3-thienylmethyl ester

[0880] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) and3-thiophenemethanol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[0881] NMR data was as follows:

[0882]¹H-nmr (CDCl₃): δ=8.03 (bd, J=9 Hz, 1H), 7.56-7.5 (m, 1H), 7.47(bs, 1H), 7.4-7.17 (m, 4H), 7.06 (d, J=9 Hz, 1H), 5.1 (s, 2H), 4.3 (dq,1H), 1.3 (d, J=9 Hz, 3H).

Example A43 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-methylcyclopentyl ester

[0883] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) and2-methylcyclopentanol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[0884] NMR data was as follows:

[0885]¹H-nmr (CDCl₃): δ=7.39-7.16 (m, 4H), 6.3 (bd, 1H), 4.79-4.7 (m,1H), 4.6-4.25 (m, J=9 Hz, 1H), 3.577 (s, 2H), 2.09-1.8 (m, 2H), 1.74-1.6(m, 2H), 1.39 (dd, J=9 Hz, 3H), 1.2 (dt, J=9 Hz, 1H), 0.979 (dd, J=9 Hz,2H)

[0886] C₁₇H₂₂NO₃Cl (MW=323.82, Mass Spectroscopy (MH⁺323).

Example A44 Synthesis of N-[(3-chlorophenyl)acetyl]alanine2-methylprop-2enyl ester

[0887] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) and2-methylprop2-en-1-ol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[0888] NMR data was as follows:

[0889]¹H-nmr (CDCl₃): δ=7.39-7.16 (m, 4H), 6.03 (bs, 1H), 4.77 (s, 2H),4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 (s, 3H), 1.43 (d, J=9 Hz, 3H)

[0890] C₁₅H₁₈NO₃Cl (MW=295.76, Mass Spectroscopy (MH⁺295)).

Example A45 Synthesis of N-[(3-chlorophenyl)acetyl]alaninecyclohex-2-enyl ester

[0891] Following General Procedure C′ above, and usingN-(3-chlorophenylacetyl alanine (from Example D′ above) andcyclohex-2-en-1-ol (Aldrich) the title compound can be prepared. Thereaction was monitored by tlc on silica gel and purification was byliquid chromatography using 3:7 EtOAc:hexane as the eluant.

[0892] NMR data was as follows:

[0893]¹H-nmr (CDCl₃): δ=8.6 (bd, J=9 Hz, 1H), 7.4-7.2 (m, 4H), 6.0-5.8(m, 1H), 5.7-5.5 (m, 1H), 5.1 (bs, 1H), 4.13-4.29 (m, 1H), 3.5 (s, 2H),2.1-1.9 (m, 2H), 1.8-1.69 (m, 1H), 1.69-1.49 (m, 4H), 1.3 (dd, J=9 Hz,3H)

[0894] C₁₇H₂₀NO₃Cl (MW=321.8, Mass Spectroscopy (MH⁺321.2)).

Example A46 Synthesis of N-[(2-phenylbenzoxazol-5-yl)acetyl]alanineiso-butyl ester

[0895] Following General Procedure I′ above, and using5-(2-phenylbenzoxazol)-yl-acetic acid (CAS#62143-69-5) and alanineiso-butyl ester (prepared following General Procedure J′ above), thetitle compound was prepared.

[0896] NMR data was as follows:

[0897]¹H-nmr (CDCl₃): δ=8.24 (m, 3H), 7.68 (m, 1H), 7.51 (m, 5H), 6.04(m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, 1H), 1.35 (d,3H), 0.87 (d, 6H).

[0898] C₂₂H₂₄N₂O₄ (MW=380, Mass Spectroscopy (MH⁺381)).

Example 47 Synthesis of N-[(3-methylthiophenyl)acetyl]alanine iso-butylester

[0899] Following General Procedure I′ above, and using3-methylthiophenylacetic acid (CAS#18698-73-2) and alanine iso-butylester (prepared following General Procedure J′ above), the titlecompound was prepared. The reaction was monitored by tlc on silica geland purification was by filtration as described in the generalprocedure.

[0900] NMR data was as follows:

[0901]¹H-nmr (CDCl₃): δ=7.14 (m, 2H), 7.01 (m, 1H), 4.56 (m, 11), 3.88(m, 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89 (m, 1H), 1.35 (d, 3H) 0.85 (d,6H).

[0902] C₁₆H₂₃NO₃S (MW=309, Mass Spectroscopy (MH⁺310)).

Example A48 Synthesis of N-4[(2-furyl)acetyl]alanine iso-butyl ester

[0903] Following General Procedure I′ above, and using 2-furylaceticacid (CAS#2745-26-8) and alanine iso-butyl ester (prepared followingGeneral Procedure J′ above), the title compound was prepared. Thereaction was monitored by tlc on silica gel and purification was byfiltration as described in the general procedure.

[0904] NMR data was as follows:

[0905]¹H-nmr (CDCl₃): δ=7.36 (m, 1H), 6.34 (m, 1H), 6.21 (m, 1H), 4.56(m, 1H), 3.91 (m, 2H), 3.61 (s, 2H), 1.92 (m, 1H), 1.38 (d, 3H) 0.89 (d,61).

[0906] C₁₃H₁₉NO₄ (MW=253, Mass Spectroscopy (MH⁺254)).

Example A49 Synthesis of N-[(benzofuran-2-yl)acetyl]alanine iso-butylester

[0907] Following General Procedure I′ above, and usingbenzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0908] NMR data was as follows:

[0909]¹H-nmr (CDCl₃): δ=7.51 (m, 1H), 7.44 (m, 1H),7.25 (m, 2H), 6.67(s, 1H), 4.60 (m, 1H), 3.87 (m, 2H), 3.77 (s, 2H), 1.88 (m, 1H), 1.38(d, 3H), 0.87 (d, 6H).

[0910] C₁₇H21NO₄ (MW=303, Mass Spectroscopy (MH⁺304)).

Example A50 Synthesis of N-[(benzothiophen-3-yl)acetyl]alanine iso-butylester

[0911] Following General Procedure I′ above, and usingthianaphthen-3-ylacetic acid (Lancaster) and alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0912] NMR data was as follows:

[0913]¹H-nmr (CDCl₃): δ=7.89 (m, 1H), 7.76 (m, 1H), 7.38 (m, 3H), 6.07(m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.82 (s, 4H), 1.84 (m, 1H), 1.32(d, 3H) 0.85 (d, 6H).

[0914] C₁₇H₂₁NO₃S (MW=319, Mass Spectroscopy (MH⁺320)).

Example A51 Synthesis of N-[(2-chloro5-thienyl)acetyl]alanine iso-butylester

[0915] Following General Procedure I′ above, and using5-chloro2-thienyl)acetic acid (CAS#13669-19-7) and alanine iso-butylester (prepared following General Procedure J′ above), the titlecompound was prepared. The reaction was monitored by tlc on silica geland purification was by filtration as described in the generalprocedure.

[0916] NMR data was as follows:

[0917]¹H-nmr (CDCl₃): δ=6.77 (m, 1H), 6.68 (d, 1H), 6.31 (bm, 1H), 4.59(m, 1H), 3.91 (m, 2H), 3.38 (s, 2H), 1.90 (m, 1H), 1.39 (d, 3H) 0.89 (d,6H).

[0918] C₁₃H₁₈NO₃SCl (MW=303, Mass Spectroscopy (MH⁺303)).

Example A52 Synthesis of N-[(3-methylisoxazol-5-yl)acetyl]alanineiso-butyl ester

[0919] Following General Procedure I′ above, and using(3-methyl-isoxazol-5-yl)acetic acid (CAS#19668-85-0) and alanineiso-butyl ester (prepared following General Procedure J′ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[0920] NMR data was as follows:

[0921]¹H-nmr (CDCl₃): δ=6.07 (s, 2H), 4.56 (m, 1H), 3.92 (m, 2H), 3.68(s, 2H), 2.29 (s, 3H), 1.94 (m, 1H), 1.89 (d, 3H) 0.91 (d, 6H).

[0922] C₁₃H₂₀N₂O₄ (MW=268, Mass Spectroscopy (MH⁺269)).

Example A53 Synthesis of N-[(2-phenylthiothienyl)acetyl]alanineiso-butyl ester

[0923] Following General Procedure I′ above, and using(2-phenyl-thiothienyl)acetic acid and alanine iso-butyl ester (preparedfollowing General Procedure J′ above), the title compound was prepared.The reaction was monitored by tlc on silica gel and purification was byfiltration as described in the general procedure.

[0924] NMR data was as follows:

[0925]¹H-nmr (CDCl₃): δ=7.21-7.11 (m, 6H), 6.92 (d, 1H), 4.56(m, 1H),3.87 (m, 2H), 3.72 (s, 2H), 1.94 (m, 1H), 1.38 (d, 3H) 0.89 (d, 6H).

[0926] C₁₉H₂₃NO₃S₂ (MW=377, Mass Spectroscopy (MH⁺378)).

Example A54 Synthesis of N-[(6imethoxybenzothiophen-2yl)acetyl]alanineiso-butyl ester

[0927] Following General Procedure I′ above, and using(6-methoxythianaphthen-2-yl)acetic acid and alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0928] NMR data was as follows:

[0929]¹H-nmr (CDCl₃): δ=7.59 (d, 1H), 7.33 (d, 1H), 7.16 (s, 1H), 7.03(dd, 1H), 4.56 (m, 1H), 3.87(s, 3H), 3.84 (m, 2H), 3.76 (s, 2H),1.85 (m,1H), 1.30 (d, 3H) 0.86 (d, 6H).

[0930] C₁₈H₂₃NO₄S (MW=349, Mass Spectroscopy (MH⁺350)).

Example A55 Synthesis ofN-[(3-phenyl-1,2,4thiadiazol-5-yl)acetyl]alanineiso-butyl ester

[0931] Following General Procedure I′ above, and using(3-phenyl-1,2,4-thiadiazol-5-yl)acetic acid (CAS#90771-06-5) and alanineiso-butyl ester (prepared following General Procedure J′ above), thetitle compound was prepared. The reaction was monitored by tlc on silicagel and purification was by filtration as described in the generalprocedure.

[0932] NMR data was as follows:

[0933]¹H-nmr (CDCl₃): δ=7.47 (m, 5H), 4.66 (m, 1H), 4.16 (s, 2H), 3.91(m, 2H), 1.93 (m, 1H), 1.48 (d, 3H) 0.93 (d, 6H).

[0934] C₁₇H₂₁N₃O₃S (MW=347, Mass Spectroscopy (MH⁺348)).

Example A56 Synthesis of N-[2-phenyloxazol-4yl)acetyl]alanine iso-butylester

[0935] Following General Procedure I′ above, and using(2-phenyloxazol-4-yl)acetic acid (CAS#22086-89-1) and alanine iso-butylester (prepared following General Procedure J′ above), the titlecompound was prepared. The reaction was monitored by tlc on silica geland purification was by filtration as described in the generalprocedure.

[0936] NMR data was as follows:

Example A57 Synthesis of N-[(3-methylphenyl)acetyl]alanine iso-butylester

[0937] Following General Procedure I′ above, and using3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0938] NMR data was as follows:

[0939]¹H-nmr (CDCl₃): δ=7.21 (m, 1H), 7.07 (m, 3H), 4.54 (m, 1H), 3.83(m, 2H), 3.52 (s, 2H), 2.35 (s, 3H), 1.87 (m, 1H), 1.32 (d, 3H), 0.88(d, 6H).

[0940] C₁₆H₂₃NO₃ (MW=277, Mass Spectroscopy (MH⁺278)).

Example A58 Synthesis of N-[(2,5-difluorophenyl)acetyl]alanineiso-butylester

[0941] Following General Procedure I′ above, and using2,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0942] NMR data was as follows:

[0943]¹H-nmr (CDCl₃): δ=7.08-6.94 (m, 3H), 4.57 (m, 1H), 3.91 (m, 2H),3.56 (s, 2H), 1.92 (m, 1H), 1.41 (d, 3H) 0.91 (d, 6H).

[0944] C₁₅H₁₉NO₃F₂ (MW=299, Mass Spectroscopy (MH⁺300)).

Example A59 Synthesis of N-[(3,5-diflurophenyl)acetyl]alanine iso-butylester

[0945] Following General Procedure I′ above, and using3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0946] NMR data was as follows:

[0947]¹H-nmr (CDCl₃): δ=6.81 (m, 2H), 6.74 (m, 1H), 6.06 (m, 1H), 4.57(m, 11H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, 1H), 1.36 (d, 3H) 0.87(d, 6H).

[0948] C₁₅H₁₉NO₃F₂ (MW=299, Mass Spectroscopy (MH⁺300)).

Example A60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester

[0949] Following General Procedure I′ above, and using 3-thiopheneaceticacid (Aldrich) and alanine iso-butyl ester (prepared following GeneralProcedure I′ above), the title compound was prepared. The reaction wasmonitored by tlc on silica gel and purification was by filtration asdescribed in the general procedure.

[0950] NMR data was as follows:

[0951]¹H-nmr (CDCl₃): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09(m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37(d, 3H) 0.92 (d, 6H).

[0952] Optical Rotation: [α]₂₃−52 (c 1 MeOH) @589 nm.

[0953] C₁₃H₁₉NO₃S (MW=269, Mass Spectroscopy (MH⁺269)).

Example A61 Synthesis of N-[(4methylphenyl)acetyl]-L-alanine iso-butylester

[0954] Following General Procedure I′ above, and using4-methylphenylacetic acid (Aldrich) and L-alanine iso-butyl ester(prepared following General Procedure J′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel andpurification was by filtration as described in the general procedure.

[0955] NMR data was as follows:

[0956]¹H-nmr (CDCl₃): δ=7.11 (s, 4H), 5.93 (m, 1H), 4.58 (m, 1H), 3.88(m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89 (m, 1H), 1.32 (d, 3H), 0.89(d, 6H). C₁₆H₂₃NO₃ (MW=277.35, Mass Spectroscopy (MH⁺278)).

Example A62 Synthesis of N-(phenylacetyl)-L-alanineS-1-(methoxycarbonyl) iso-butyl ester

[0957] Following General Procedure K′ and using(S)-(+)-2-hydroxy-2-methylbutyric acid (Aldrich) in place of the aminoacid, methyl (S)-(+)-2-hydroxy-2-methylbutyrate was prepared.

[0958] Methyl (S)-(+)-2-hydroxy-2-methylbutyrate was then coupled withcarbobenzyloxy-L-alanine (Aldrich) using General Procedure E′ to providecarbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl ester.

[0959] Carbobenzyloxy-L-alanine S-1-(methoxycarbonyl) iso-butyl ester(1.0 g) was then dissolved in 20 mL of methanol and 6N HCl (0.5 mL) and10% palladium on carbon (0.1 g) were added. This reaction mixture washydrogenated at 40 psi of hydrogen on a Parr apparatus for 5 hours atroom temperature and then filtered through a pad of Celite. The filtratewas concentrated at reduced pressure to provide L-alanineS-1-(methoxycarbonyl) iso-butyl ester hydrochloride (98% yield).

[0960] L-Alanine S-1-(methoxycarbonyl) iso-butyl ester hydrochloride wasthen coupled to phenylacetic acid using General Procedure G′ to providethe tide compound.

[0961] NMR data was as follows:

[0962]¹H-nmr (CDCl₃): δ=7.35 - 7.20 (m, 5H), 6.22 (bd, 1H), 4.83 (d,1H), 4.65 (p, 1H), 3.68 (s, 3H), 3.55 (s, 2H), 2.21 (m, 1H), 1.40 (d,3H), 0.97 (d, 3H), 0.93 (d, 3H).

[0963]¹³C-nmr (CDCl₃): δ=173.25, 171.18, 170.22, 135.11, 129.94, 129.50,127.88, 52.67, 48.49, 43.98, 30.53, 19.21, 18.75, 17.58.

Example A63 Synthesis of N-[(3-nitrophenyl)acetyl]-L-alanine iso-butylester

[0964] Following General Procedure H′ above and using3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl esterhydrochloride (from Example B′ above), the title compound was prepared.The reaction was monitored by tlc on silica gel and purification was byrecrystallization from butyl chloride.

[0965] NMR data was as follows:

[0966]¹H-nmr (CDCl): δ=8.17 (m, 2H), 7.68 (d, 1H), 7.52 (t, 1H), 6.18(m, 1H), 4.48 (m, 1H), 3.94 (m, 2H), 3.67 (s, 2H), 1.93 (m, 1H), 1.42(d, 3H), 0.91 (d, 3H).

[0967] Optical Rotation: [Ε]₂₃−49 (c 5, MeOH).

Example A64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethylester

[0968] Following General Procedure G′ and using 3,5-difluorophenylaceticacid (Aldrich) and alanine ethyl ester (Aldrich), the title compound wasprepared as a solid with a melting point of 93°-95° C. The reaction wasmonitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was bychromatography on silica gel using EtOAc as the eluant followed byrecrystallization from 1-chlorobutane.

[0969] NMR data was as follows:

[0970]¹H-nmr (DMSO-d₆): δ=1.30 (d, 3H); 3.52 (s, 2H).

[0971] C₁₃H₁₅NO₃F₂ (MW=271.26, Mass Spectroscopy (MH⁺271)).

Example A65 Synthesis of N-[(3-nitrophenyl)acetyl]methionine ethyl ester

[0972] Following General Procedure G′ above and using3-nitrophenylacetic acid (Aldrich) and methionine ethyl esterhydrochloride (Aldrich), the title compound was prepared. The reactionwas monitored by tlc on silica gel and purification was byrecrystallization from butyl chloride.

[0973] NMR data was as follows:

[0974]¹H-nmr (CDCl₃): δ=8.18 (s, 1H), 8.15 (d, 1H) 7.66 (d, 1H), 7.48(t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47(t, 2H), 2.12 (m, 2 H), 2.08 (s, 3H), 1.27 (t, 3H).

[0975] Optical Rotation: [α]₂₃−30 (c 5, MeOH).

Example A66 Synthesis of N-[(3-chlorophenyl)acetyl]alanine iso-butylester

[0976] Following General Procedure G′ above and using3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester(prepared following General Procedure I′ above), the title compound wasprepared. The reaction was monitored by tlc on silica gel.

[0977] NMR data was as follows:

[0978]¹H-nmr (CDCl₃): δ=7.29 (m, 3H), 7.18 (m, 1H), 6.0 (m, 1H), 4.56(m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.39 (d, 3 H), 0.91(d, 3H).

[0979] Optical Rotation: [α]₂₃−45 (c 5, MeOH).

[0980] C₁₅H₂₀NO₃Cl (MW=297.78, Mass Spectroscopy (MH⁺297)).

Example A67 Synthesis of N-[(3-chlorophenyl)acetyl]alaliine2-(N,N-dimethylamino)ethyl ester

[0981] Following General Procedure C′ above, and usingN-(3-chlorophenyl-acetyl)alanine (from Example D′ above) and2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can beprepared. The reaction was monitored by tlc on silica gel andpurification was by liquid chromatography using 0.1:2:0.79NH₄OH:EtOH:CHCl₃ as the eluant.

[0982] NMR data was as follows:

[0983]¹H-nmr (CDCl₃): 7.37 (s, 1H), 7.33-7.2 (m, 3H), 4.675-4.6 (m, 1H),4.5-4.37 (m, 1H), 4.25-4.13 (m, 1H), 3.6 (d, J=7 Hz, 2H), 2.86 (bs, 2H),2.3 (s, 6H), 1.23 (d, J=9 Hz, 3H).

[0984] C₁₅H₂₁N₂O₃Cl (MW=313.799, Mass Spectroscopy (M+313)).

Example A68 Synthesis of 2-[(3,5-dichlorophenyl)acetamido]hexanoic acidmethyl ester

[0985] Following General Procedure F′ above, an using3,5-dichlorophenylacetic acid (from Example C′ above) and L-norleucinemethyl ester hydrochloride (Bachem), the tide compound was prepared as asolid having a melting point of 77°-78° C. The reaction was monitored bytlc on silica gel (Rf=0.70 in 40% EtOAC/hexanes) and purification was byflash chromatography on silica gel using 40% EtOAc/hexanes as theeluant.

[0986] NMR data was as follows:

[0987]¹H-nmr (CDCl₃): δ=7.20 (s), 7.18 (s), 6.6 (m), 4.55 (m), 3.7 (s),3.5 (s), 3.4 (s), 2.0 (s), 1.8 (m), 1.6 (m), 1.2 (m), 0.8 (t).

[0988]¹³C-nmr (CDCl₃): δ=173.54, 169.67, 138.43, 135.72, 128.33, 128.07,78.04, 77.62, 77.19, 53.04, 52.90, 43.14, 32.57, 27.87, 22.81, 14.41.

Example A69 Synthesis of N-[(3,5-diclorophenyl)acetyl]-L-alanineiso-butyl ester

[0989] Following General Procedure F′ above, and using3,5-dichlorophenylacetic acid (from Example C′ above) and L-alanineiso-butyl ester hydrochloride (from Example B′ above), the titlecompound was prepared as a solid having a melting point of 115′-116° C.The reaction was monitored by tlc on silica gel (Rf=0.40 in 3%methanol/dichloromethane) and purification was by flash chromatographyon silica gel using 3% methanol/dichloromethane as the eluant.

[0990] NMR data was as follows:

[0991]¹H-nmr (CDCl₃): δ=7.27 (d, J=2 Hz, 1H), 7.19 (s, 2H), 6.22 (d, J=6Hz, 1H), 4.59 (quint., J=7 Hz, 1H), 3.9 (q, J=4 Hz, 2H), 3.5 (s, 2H),1.9 (m, 1H), 1.4 (d, J=7 Hz, 3H), 0.91 (d, J=7 Hz, 6H).

[0992]¹³C-nmr (CDCl₃): δ=173.45, 169.37, 138.31, 135.75, 128.39, 128.11,78.04, 77.61, 77.19, 72.19, 54.03, 48.97, 43.12, 28.24, 19.52, 19.49,19.09.

[0993] C₁₅H₁₉NO₃Cl₂ (MW=331.9, Mass Spectroscopy (MH⁺332)).

Example A70 Synthesis of N-(cyclohexyIacetyl)-L-alanine iso-butyl ester

[0994] Following General Procedure B′ above, and using cyclohexylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleB′ above), 5 the title compound was prepared as a solid having a meltingpoint of 92° C.-93° C. The reaction was monitored by tlc on silica gel(Rf=0.39 in 1:3 EtOAc:hexane) and purification was by extraction withEtO followed by washes with aqueous K₂CO₃ and aqueous HCl.

[0995] NMR data was as follows:

[0996]¹H-nmr (CDCl₃): δ=0.93 (d, J=6.7 Hz, 6H), 0.85-1.01 (m, 2H),1.05-1.35 (m, 3H), 1.40 (d, J=7.1 Hz, 3H), 1.60-1.85 (m, 6H), 1.95 (m,1H), 2.06 (d, J=7.0 Hz, 2H), 3.92 (m, 2H), 4.61 (m, 1H), 6.08 (bd, 1H).

[0997]¹³C-nmr (CDCl₃): δ=18.7, 18.9, 26.0, 26.1, 27.6, 33.0, 35.3, 44.6,47.9, 71.4, 171.8, 173.3.

[0998] C₁₅H₂₇NO₃ (MW=269.39, Mass Spectroscopy (MH⁺270)).

Example A71 Synthesis of N-(cyclopentylacetyl)-L-alanine iso-butyl ester

[0999] Following General Procedure B′ above, and using cyclopentylaceticacid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from ExampleB′ above), the title compound was prepared as a solid having a meltingpoint of 62° C.-64° C. The reaction was monitored by tlc on silica gel(Rf=0.37 in 1:3 EtOAc:hexane) and purification was by extraction withEt₂O followed by washes with aqueous K₂CO₃ and aqueous HCl.

[1000] NMR data was as follows:

[1001]¹H-nmr (CDCl₃): δ=0.87 (d, J=6.8 Hz, 6H), 1.01-1.17 (m, 2H), 1.34(d, J=7.2 Hz, 3H), 1.40-1.62 (m, 4H), 1.70-1.83 (m, 2H), 1.89 (m, 1H),2.15 (m, 3H), 3.86 (m, 2H), 4.55 (m, 1H), 6.30 (d, J=7.1 Hz, 1H).

[1002]¹³C-nmr (CDCl₃): δ=18.4, 18.78, 18.80, 24.8 (very high), 27.5,32.27, 32.32, 36.9, 42.5, 47.7, 71.2, 172.2, 173.2.

[1003] Elemental Analysis-Calc (%): C, 65.85; H, 9.87; N, 5.49; Found(%): C, 66.01; H, 10.08; N, 5.49.

[1004] C₁₄H₂₅NO₃ (MW=255.36, Mass Spectroscopy (MH⁺256)).

Example A72 Synthesis of N-[(cyclohex-1enyl)acetyl]-L-alanine iso-butylester

[1005] Following General Procedure B′ above, and using cyclohex-lenylacetic acid (Alfa) and L-alanine iso-butyl ester hydrochloride (fromExample B′ above), the title compound was prepared as a solid having amelting point of 49° C.-51° C. The reaction was monitored by tlc onsilica gel (Rf=0.40 in 1:3 EtOAc:hexane) and purification was byextraction with Et₂O followed by washes with aqueous K₂CO₃ and aqueousHCl.

[1006] NMR data was as follows:

[1007] H-nmr (CDCl₃): δ=0.91 (d, J 4.5 Hz, 3H), 0.93 (d, J=6.7 Hz, 3H),1.40 (d, J=7.2 Hz, 3H), 1.52-1.70 (m, 4H), 1.97 (m, 3H), 2.06 (bs, 2H),2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m, 1H), 5.65 (s, 1H), 6.33 (d, J=6.6Hz, 1H).

[1008]¹³C-nmr (CDCl₃): δ=18.7, 18.91, 18.93, 21.9, 22.7, 25.3, 27.6,28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1.

[1009] Elemental Analysis-Calc (%): C, 67.38; H, 9.42; N, 5.24; Found(%): C, 67.34; H, 9.54; N, 5.16.

[1010] C₁₅H₂₅NO₃ (MW=267.37, Mass Spectroscopy (MH⁺268)).

Example A73 Synthesis of N-[(3-chlorophenyl)acetyl]alanine3-methylbut-2-enyl thioester

[1011] Following General Procedure C′ above, and usingN-[(3-chlorophenyl)acetyl]alanine and 3-methyl-2-butene thioester (TCI),the title compound can be prepared. The reaction was monitored by tlc onsilica gel and purification was by liquid chromatography using 3:7EtOAc:Hexane as the eluant.

[1012] NMR data was as follows:

[1013]¹H-nmr (DMSO-d₆): δ=5.2-5.075 (m, 1H), 4.37 (dq, J=9 Hz, 1H), 3.56(s), 3.43 (d, J=12 Hz, 2H), 1.266 (d, J=12 Hz, 6H) 1.3 (d, J=9 Hz, 3H).

[1014] C₁₆H₂₀NO₂ClS (MW=325.86, Mass Spectroscopy (M⁺325)).

Example A74 Synthesis of N-[(2-phenyl)-2-fluoroacetyl]alanine ethylester

[1015] Following General Procedure F′ above, and using α-fluorophenylacetic acid (Aldrich) and alanine ethyl ester (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc on silica gel(Rf=0.75 in 1:1 EtOAc:hexane) and purification was by chromatography onsilica gel using 1:2 ethyl acetate/hexanes as the eluent.

[1016] NMR data was as follows:

[1017]¹H-nmr (DMSO-d₆): δ=1.14 (q, 3H), 1.34 (d, 3H), 4.07 (m, 2H), 4.33(m, 1H), 5.84 (d, 1H), 6.01 (d, 1H), 7.40-7.55 (m, 5H), 8.87 (m, 1H).

[1018] C₁₃H₁₆NO₃F (MW=253.27, Mass Spectroscopy (MH⁺253)).

Example A75 Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycinemethyl ester

[1019] Following General Procedure F above, and using3,5-difluorophenylacetic acid (Aldrich) and L-phenylglycine methyl esterhydrochloride (Bachem), the title compound was prepared.

[1020] NMR data was as follows:

[1021]¹H-nmr (CDCl₃): δ=7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d 1H,7.1 Hz), 5.56 (d 1H 7 Hz), 3.72 (s 3H), 3.57 (s 2H)

[1022]¹³C-nmr (CDCl₃): δ=197.6, 177.6, 171.8, 169.3, 136.7, 129.6,129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103.5, 65.1, 57.2,53.5, 45.1, 43.3, 43.3

[1023] C₁₇H₁₅NO₃F₂ (MW=319.31, Mass Spectroscopy (MH +320)).

Example 76 Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycineiso-butyl ester

[1024] The 3,5-difluorophenylacetic acid (Aldrich) was EDC coupled toL-phenylglycine methyl ester hydrochloride (Bachem) via GeneralProcedure F above.

[1025] The resulting compound was placed in a large excess of thedesired alcohol. A catalytic amount of dry NaH was added, and thereaction was followed by tlc until the presence of starting fnmaterialwas no longer detected. The reaction was quenched with a few millilitersof 1N HCl, and after a few minutes of stirring saturated aqueous NaHCO₃was added. The volume of the reaction mixture was reduced on a rotaryevaporator until the excess alcohol was removed and then the remainingresidue was taken up in ethyl acetate and additional water was added.The organic phase was washed with saturated aqueous NaCl and dried overMgSO₄. The solution was stripped free of solvent on a rotary evaporator,and the crude product residue was then further purified bychromatography.

[1026] NMR data was as follows:

[1027]¹H-nmr (CDCl₃): δ=7.35-7.3 (m 5H), 6.8-6.7 (m 3H) 6.60 (d 1H, 7Hz), 5.55 (d 1H 7.1 Hz), 3.9 (m 2H), 3.60 (s 2H), 1.85 (m 1H 7 Hz), 0.8(q 6H 7 Hz)

[1028] 13C-nmr (CDCl₃): δ=171.3, 169.3, 165.4, 138.5, 137.0, 129.5,129.2, 127.6, 113.1, 113.0, 112.8, 112.7, 103.8, 103.5, 103.2, 75.5,57.2, 43.4, 43.3, 28.2, 19.3

[1029] C₂₀H₂₁NO₃F₂ (MW=361.39, Mass Spectroscopy (MH +362)).

Example A77 Synthesis of N-(cyclopentylacetyl)-L-phenylglycine methylester

[1030] Following General Procedure D′ above, and using cyclopentylaceticacid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem)the title compound was prepared.

[1031] NMR data was as follows:

[1032]¹H-nmr (CDCl₃): δ=7.35 (s, 5H), 6.44 (bd, 1H), 5.6 (d, 1H), 3.72(s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05 (m, 2H)

[1033]¹³C-nmr (CDCl₃): δ=172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2,52.7, 42.5, 36.9, 32.40, 32.38, 24.8

Example A78 Synthesis of N-(cyclopentylacetyl)-Lalanie methyl ester

[1034] Following General Procedure D′ above, and using cyclopentylaceticacid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma) thetitle compound was prepared.

[1035] NMR data was as follows:

[1036]¹H-nmr (CDCl₃): δ=6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13(bs, 3H), 1.80-1.00 (m (includes d at 1.30, 3H), 11H)

[1037]¹³C-nmr (CDCJ₃): δ=173.7, 172.5, 52.1, 47.6, 42.3, 36.8, 32.15,32.14, 18.0

[1038] C₁₁H₁₉NO₃ (MW=213.28, Mass Spectroscopy (MH⁺214)).

Example A79 Synthesis of N-(cyclopropylacetyl)-L-phenylglycine methylester

[1039] Following General Procedure D′ above, and using cyclopropylaceticacid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem),the title compound was prepared.

[1040] NMR data was as follows:

[1041]¹H-nmr (CDCl₃): δ=7.35 (m, 5H) 6.97 (bd, J=7.2 Hz, 1H) 5.59 (d,J=7.8 Hz, 1H), 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, 1H), 0.62 (m,2H), 0.02 (m, 2H)

[1042]¹³C-nmr (CDCl₃): δ=171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1,52.7, 41.0, 6.9, 4.37, 4.33

Example A80 Synthesis of N-(cyclopropylacetyl)-L-alanine methyl ester

[1043] Following General Procedure D′ above, and using cyclopropylaceticacid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), thetitle compound was prepared.

[1044] NMR data was as follows:

[1045]¹H-nmr (CDCl₃): δ=6.60 (d, 1H), 4.55 (m, 1H), 3.69 (s, 3H), 2.10(m, 2H), 1.34 (d, 3H), 0.95 (m, 11H), 0.58 (m, 2H) 0.15 (m, 2H)

[1046]¹³C-nmr (CDCl₃): δ=173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7,4.27, 4.22

Example A81 Synthesis of N-[(3-nitrophenyl)acetyl]-L-methionineiso-butyl ester

[1047] Following General Procedure H′ above, and using nitrophenylaceticacid (Aldrich) and L-methionine (Aldrich), the title compound wasprepared as a tan oil. The reaction was monitored by tlc on silica gel.

[1048] NMR data was as follows:

[1049] 1H-nmr (CDCl₃): δ=8.16 (m,2H) 7.67 (d,1H) 7.32 (t, 1H), 6.31 (bd,1H), 4.69 (m, 1H), 3.90 (d, 2H), 3.68 (s, 2H), 2.47 (t, 2H), 2.15 (m,1H), 2.02 (s, 3H), 1.90 (m, 2H), 0.91 (d, 6H).

[1050] C₁₇H₂₄N₂O₅S (MW=368.4, Mass Spectroscopy (MH⁺368)).

[1051] The following General Procedures A″-B″ and Examples B1-B2illustrate the synthesis of N-(aryl/heteroarylacetyl)amino acid startingmaterials useful in this invention. Other N-(aryl/heteroarylacetyl)aminoacids can be prepared using these procedures from commerically availableor known starting materials.

GENERAL PROCEDURE A″ Acid Chloride Preparation

[1052] 3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) wasdissolved in dichloromethane and this solution was cooled to 0° C. DMF(0.5 mL, catalytic) was added followed by the dropwise addition ofoxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reactionwas stirred for 3 h and then rotoevaporated at reduced pressure to aresidue which was placed on a high vacuum pump for 1 h to afford3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acidchlorides can be prepared in a similar manner.

GENERAL PROCEDURE B″ Schotten-Bauman Procedure

[1053] 3,5-Difluorophenylacetyl chloride (from General Procedure A″) wasadded dropwise to a 0° C. solution of L-alanine (Aldrich) (16.7 g, 0.187mol) in 2 N sodium hydroxide (215 mL, 0.43 mol). The reaction wasstirred for 1 h at 0° C. and then overnight at room temperature. Thereaction was diluted with water (100 mL), then extracted with ethylacetate (3×150 mL). The organic layer was then washed with brine (200mL), dried over MgSO₄, and rotoevaporated at reduced pressure to aresidue. Recrystallization of the residue from ethyl acetate/hexanesafforded the desired product (34.5 g, 82% yield). Other acid chloridesmay be used in this procedure to provide for intermediates useful inthis invention.

Example B1 Synthesis of N-(Phenylacetyl)-L-alanine

[1054] Following General Procedure B″ above, title compound was preparedfrom phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solidhaving a melting point of 102-104° C.

[1055] NMR data was as follows:

[1056]¹H-nmr (CDCl₃): δ=9.14 (br s, 1H), 7.21-7.40 (m, 5H), 6.20 (d,J=7.0 Hz, 1H), 4.55 (m, 1H), 3.61 (s, 2H), 1.37 (d, J=7.1 Hz, 3H).

[1057]¹³C-nmr (CDCl₃): δ=176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2,17.9.

Example B2 Synthesis of N-(3,5-Difluorophenylacetyl)-L-alanine

[1058] Following General Procedure B″ above, the title compound wasprepared from 3,5-difluorophenylacetyl chloride (from General ProcedureA″ above) and L-alanine (Aldrich).

[1059] NMR data was as follows:

[1060]¹H-nmr (CD₃OD): δ=8.32 (br s, 0.3H), 6.71 (m, 2H), 6.60 (m, 1H),4.74 (br s, 1.7H), 4.16 (m, 1H), 3.36 (s, 2H), 1.19 (d, J=7.3 Hz, 3H).

[1061]¹³C-nmr (CD₃OD): δ=175.9, 172.4, 164.4 (dd, J=13.0, 245.3 Hz),141.1, 113.1 (dd, J=7.8, 17.1 Hz), 102.9 (t, J=25.7 Hz), 49.5, 42.7,17.5.

[1062] The following General Procedures A′″-C′″ and Examples C1-C8illustrate the synthesis of dipeptide ester starting materials useful inthis invention. Other dipeptide esters can be prepared using theseprocedures from commerically available or known starting materials.

GENERAL PROCEDURE A′″ EDC Coupling Procedure

[1063] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at 0° C. or room temperature was charged withTHF, carboxylic acid (1.0 eq), an amine or amine hydrochloride (1.1eq.), 1-hydroxybenzotriazole hydrate (1.15-1.2 eq.),N,N-diisopropylethylamine (2.2-2.9 eq.), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)(1.15-1.2 eq.). The cooling bath was removed and the mixture allowed towarm to room temperature with stirring for 10-20 hours. The mixture wasdiluted with EtOAc and washed with 0.5 N aqueous HCl (2×), diluteaqueous NaHCO₃ (1×x), brine (1×) and dried over either Na₂SO₄ or MgSO₄.The drying agent was removed by filtration and the filtrate concentratedin vacuo. The residue was either used without further purification orpurified using standard procedures, such as flash chromatography onsilica gel and/or recrystallization.

GENERAL PROCEDURE B′″ Removal of the N-tert-Boc Protecting Group

[1064] The N-tert-Boc-amine was dissolved in a suitable dry solvent(such as 1,4-dioxane or ethyl acetate) and the solution was cooled in anice bath. Gaseous HCl was introduced into the solution until the mixturewas saturated with HCl. The mixture was then stirred until the reactionwas complete. The resulting mixture was concentrated under reducedpressure to yield the amine hydrochloride. The amine hydrochloride wasused without purification or was triturated using, for example, diethylether and the resulting solid was collected by filtration.

GENERAL PROCEDURE C′″ EEDO Coupling Procedure

[1065] A round bottom flask containing a magnetic stir bar under asatmosphere of nitrogen at room temperature was charged with THF, acarboxylic acid (1 eq.), an amine hydrochloride (1.1 eq.), and2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) (1.1 eq). Thereaction mixture was allowed to stir for 15 minutes and then4-methylmorpholine (1.1 eq) was added and stirring was continued at roomtemperature for 15-20 hours. The reaction mixture was concentrated invacuo and the resulting residue was partitioned between ethyl acetateand water. The organic phase was separated and washed with saturatedaqueous NH₄Cl (2×), saturated aqueous NaHCO₃ (2×), followed by brine(lx). The organic phase was then dried over Na₂SO₄ and the drying agentwas removed by filtration and the filtrate concentrated in vacuo. Theresidue was either used without further purification or purified usingstandard procedures, such as flash chromatography on silica gel and/orrecrystallization.

Example C1 Synthesis of S N-(L-Methionine)-L-phenylglycine Methl EsterHydrochloride

[1066] Following General Procedure A′″ and usingN-(tert-butoxycarbonyl)-L-methionine (Sigma) and L-phenylglycine methylester hydrochloride (Bachem), the Boc-protected dipeptide was preparedas a crude solid or foam. The resulting crude dipeptide was deprotectedusing General Procedure B′″ to afford the title compound as a crudesolid or foam.

Example C2 Synthesis of N-(2-Aminobutanoyl)-L-phenylglycine Methl EsterHydrochloride

[1067] Following General Procedure A′″ and usingN-(tert-butoxycarbonyl)-2-aminobutyric acid (Sigma) and L-phenylglycinemethyl ester hydrochloride (Bachem), the Boc-protected dipeptide wasprepared as a crude solid or foam. The resulting crude dipeptide wasdeprotected using General Procedure B′″ to afford the title compound asa crude solid or foam.

Example C3 Synthesis of N-(L-Leucine)-L-phenylglycine Methl EsterHydrochloride

[1068] Following General Procedure A′″ and usingN-(tert-butoxycarbonyl)-L-leucine (Sigma) and L-phenylglycine methylester hydrochloride (Bachem), the Boc-protected dipeptide was preparedas a crude solid or foam. The resulting crude dipeptide was deprotectedusing General Procedure B′″ to afford the title compound as a crudesolid or foam.

Example C4 Synthesis of N-(L-Phenylalanine)-L-phenylglycine Methl EsterHydrochloride

[1069] Following General Procedure A. and usingN-(tert-butoxycarbonyl)-L-phenylalanine (Sigma) and L-phenylglycinemethyl ester hydrochloride (Bachem), the Boc-protected dipeptide wasprepared as a crude solid or foam. The resulting crude dipeptide wasdeprotected using General Procedure B′″ to afford the title compound asa crude solid or foam.

Example C5 Synthesis of N-(Glycine)-Lphenylglycine Methl EsterHydrochloride

[1070] Following General Procedure A′″ and usingN-(tert-butoxycarbonyl)glycine (Sigma) and L-phenylglycine methyl esterhydrochloride (Bachem), the Boc-protected dipeptide was prepared as acrude solid or foam. The resulting crude dipeptide was deprotected usingGeneral Procedure B′″ to afford the title compound as a crude solid orfoam.

Example C6 Synthesis of N-(L-Phenylglycine)-L-phenylglycine Methl EsterHydrochloride

[1071] Following General Procedure C′″ and usingN-(tert-butoxycarbonyl)-L-phenylalanine (Sigma) and L-phenylglycinemethyl ester hydrochloride (Bachem), the Boc-protected dipeptide wasprepared as a crude solid or foam. The resulting crude dipeptide wasdeprotected using General Procedure B′ to afford the title compound as acrude solid or foam.

Example C7 Synthesis of N-(L-Valine)-L-phenylglycine Methl EsterHydrochloride

[1072] Following General Procedure A′″ and usingN-(tert-butoxycarbonyl)-L-valine (Sigma) and L-phenylglycine methylester hydrochloride (Bachem), the Boc-protected dipeptide was preparedas a crude solid or foam. The resulting crude dipeptide was deprotectedusing General Procedure B′″ to afford the title compound as a crudesolid or foam.

Example C8 Synthesis of N-[(S)-2-Aminocyclohexylacetyl)-L-phenylglycineMethl Ester Hydrochloride

[1073] Following General Procedure A′″ and usingN-(tert-butoxycarbonyl)-(S)-aminocyclohexylacetic acid (e.g.,Boc-L-cyclohexylglycine) and L-phenylglycine methyl ester hydrochloride(Bachem), the Boc-protected dipeptide was prepared as a crude solid orfoam. The resulting crude dipeptide was deprotected using GeneralProcedure B′″ to afford the title compound as a crude solid or foam.

[1074] The following Examples D1-D4 illustrate the synthesis of variousintermediates useful as starting materials for this invention. Similarintermediates can be prepared using these procedures and commericallyavailable or known starting materials.

Example D1 Synthesis of 3,5-Difluorophenyl-α-fluoroacetic Acid

[1075] Methyl 3,5-difluoromandelate was prepared following GeneralProcedure G below and using commmerically available 3,5-difluoromandelicacid. The resultant α-hydroxy methyl ester was fluorinated according tothe general procedure described in W. J. Middleton, et al., Org. Synth.Col. Vol. VI, 835. Specifically, a solution of diethylaminosulfurtrifluoride (1.1 eq) in CH₂Cl₂ was cooled to 0° C. and treated withmethyl 3,5-difluoromandelate (1.0 eq) as a solution in CH₂Cl₂. After 10min. the cooling bath was removed and the reaction was stirred atambient temperature for 30 min. The reaction was monitored by tlc(Rf=0.65, 1:1 ethyl acetate/hexanes). The mixture was then poured ontoice and the layers separated. The organic phase was washed withsaturated aqueous NaHCO₃ and brine. The organic layer was dried overNa₂SO₄, filtered, and concentrated in vacuo. The product was purified byLC2000 chromatograpy (180 mL/min) using 10% EtoAc/hexanes as the eluent.The resulting methyl 3,5-difluorophenyl-α-fluoroacetate was hydrolyzedby dissolving the ester in 70% aqueous dioxane and treating with lithiumhydroxide (2.0 eq.). No starting material remained by tlc after 2 h. Thedioxane was removed via rotary evaporation. The aqueous mixture wasfirst washed with ethyl acetate and then acidified with 0.01 N HCl. Theaqueous layer was extracted with ethyl acetate. The organic phase waswashed with brine, dried over Na₂SO₄, filtered, and concentrated. Thecrude solid was recrystallized from ethyl acetate/hexanes affording3,5-difluorophenyl-α-fluoroacetic acid as a white solid having a meltingpoint of 90-110° C.

[1076] C₈H₅F₃O₂ (MW=190.1); mass spectroscopy: 190.1.

Example D2 Synthesis of (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine

[1077] (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine was prepared byadding 5.0 equivalents of methyl magnesium bromide to a solution ofL-phenylglycine methyl ester hydrochloride in THF at 0 C. The reactionmixture was stirred for 1 hour and then quenched with sodiumbicarbonate. After standard work-up conditions, the residue was purifiedby silica gel chromatography using 10% MeOH/CHCl₃ as the eluent.

Example D3 Synthesis of Methyl (S)-2-Amino2-(6methoxy-2-naphthyl)acetate

[1078] (S)-2-(tert-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)aceticacid was prepared from 2-(6-methoxy-2-naphthyl)acetic acid according tothe general method described by D. A. Evans, et al., J. Amer. Chem.Soc., (1990), 112, 4011-4030. Briefly,(S)-3-(6-methoxy-2-naphthylacetyl)-4-benzyl-2-ozazolidinone wasconverted to(S)-3-[(S)-6-methoxy-2-naphthyl-α-azidoacetyl)-4-benzyl-2-ozazolidinonevia standard enolate azidation procedures using potassium1,1,1,3,3,3-hexamethyldisilazane and trimethylsilyl azide at −78° C.Treatment of the azide derivative with 3 equivalents of lithiumhydroxide in THF then provided(S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid. Reduction f thisintermediate, as its sodium salt, in 1:1 1,4-dioxane/water (0.05 M) with1 atm of hydrogen, 10% Pd/C at 25° C afforded(S)-2-azido-2-(6-methoxy-2-naphthyl)acetic acid, which was thenconverted, without isolation, to its N-Boc derivative on treatment with1.4 equivalents of di-tert-butyl dicarbonate and 0.47 equivalents ofsodium carbonate. The product was isolated by the acidification to pH 2with 1 N NaHSO₄ and extraction with three portions of ethyl acetate. Theproduct was recrystallized from ethyl acetate/hexanes to afford a whitesolid, m.p.=176° C (shrink); 197-199° C. (dec).

[1079] NMR data was as follows:

[1080]¹HMR (DMSO-d₆): δ=12.78 (s, 1H), 7.84-7.77 (m, 3H), 7.62 (d, J=8Hz, 1H), 7.49 (d, J=8 Hz, 1H), 7.31 (d, J=2 Hz, 1H), 7.17 (dd, J=9, 2Hz, 1H), 5.22 (d, J=8 Hz, 1H), 3.87 (s, 3H), 1.39 (s, 9H).

[1081] (S)-2-(tert-Butoxycarbonylamino)-2-(6-methoxy-2-naphthyl)aceticacid was then converted into the methyl ester using General Procedure Gbelow. The methyl ester was then dissolved in CH₂Cl₂ and this solutioncooled to 0° C. Trifluoroacetic acid (50 molar eq.) was added and thereaction was allowed to warm to room temperature and stirring wascontinued for 2 hrs. The reaction mixture was then concentrated and theresidue extracted into CH₂Cl₂ and washed with sodium bicarbonatesolution. The organic layer was dried over Na₂SO₄, filtered andconcentrated to yield methyl(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate.

Example D4 Synthesis of Methyl2-Amino2-(thieno[2,3-b]thiophen-2-yl)acetate

[1082] To a 3.75 mole equivalents of sodium hydride (oil free) was addedDMF and the resulting mixture was cooled to 0° C. A solution of methylthieno[2,3-b]thiophen-2-carboxylate (1 mole eq.) and methylmethylsulfinyl methyl sulfide (1.1 mole eq.) in DMF was then addeddropwise and the reaction mixture was stirred at 0° C. for 30 min andthen allowed to warm to room temperature and stirring was continued for3 h. The reaction was then quenched with methanol and the productextracted into EtOAc. The organic extracts were washed with waterfollowed by brine, and then dried over Na₂SO₄, filtered and concentratedto give a gummy brown oil. The residue was slurried in diethyl ether andthe resulting solid collected. The solid was then dissolved in hot ethylacetate and decolorizing carbon was added. The mixture was then filteredand solvent removed to give a solid, which was used without furtherpurification.

[1083] Acetic anhydride (10 mole eq.) and acetic acid (1.8 mole eq.)were mixed together and heated to 70° C. for 15 min. and then cooled to65° C. The solid sulfone from above was added in portions and thereaction was allowed to stir at 70° C. for 30 min. and then cooled andconcentrated. The resulting solid was taken up in ethyl acetate andwashed with sodium bicarbonate solution, followed by 1 N Na₂S₂O₃solution. The solution was then dried over MgSO₄, filtered andconcentrated to give methyl2-keto-2-(thieno[2,3-b]thiophen-2-yl)thioacetate as a solid, which wasused without further purification.

[1084] To the 2-keto compound (0.0165 moles) (4.0g) was added 270 mL ofmethanol and 16.5 mL of 1 N NaOH. The reaction was allowed to stir for 6h at room temperature and then methoxyamine (1.38 g, 0.0165 moles) wasadded and stirring was continued for 18 h. The reaction mixture was thenconcentrated and the residue dissolved in ethyl acetate and washed withwater. The aqueous layer was then acidified with in HCl and the oilyproduct was extracted into ethyl acetate and washed with brine. Theorganic layer was dried over MgSO₄, filtered and concentrated to give4.0 g of 2-(hydroxyimino)-2-(thieno[2,3-b]thiophen-2-yl)acetic acid as ayellow solid.

[1085] The methyl ester was then prepared using General Procedure Gbelow and the oxime was reduced to an amino group using GeneralProcedure R below to afford methyl2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate.

Example D5 Synthesis of N-Methyl-N′-BOC-Leucinamide

[1086] A solution of 0.9968 g (4 mmol) of N-BOC-leucine (Bachem) and1.2323 g (7.6 mmol) of CDI in 40 mL of THF was stirred for 1 hour, andthen 0.5402 g (8 mmol) of methylamine hydrochloride (Aldrich) and 0.8092g (8 mmol) of N-methylmorpholine were added. The mixture was stirred for16 hours, evaporated at reduced pressure to dryness, and the residue waswashed thproughly with water, 1N NaOH, water, followed by diethyl etherto yield 0.886 g (3.09 mmol, 70%) of the title compound.

Example D6 Synthesis of N-BOC-Norleucine amide

[1087] To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine(Bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate and50 mL of dichloromethane at 0° C. was added 3.45 g (1.2 mmol) of EDC.The resulting mixture was stirred at 0° C. for 1 hour and then ammoniagas was bubbled through the mixture for 10 min. The cooling bath wasallowed to warm to room temperature and the mixture stirred for 18hours. The mixture was evaporated at reduced pressure to dryness,triturated with 20% Na₂CO₃. The resulting solid was collected byfiltration and washed with water to yield 2.69 g (11.7 mmol, 78%) of thetitle compound.

Example D7 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine

[1088] The title compound was prepared by dissolving 1.98 g (0.006 mols)of N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester(from Example 85 below) in 60 mL dioxane and 15 mL of H₂O and addingLiOH (0.25 g, 0.006 mol) that has been dissolved in 15 mL of H₂O. Afterstirring for 3 hours, the dioxane was removed under reduced pressure andthe residue diluted with EtOAc, the layers were separated and theaqueous layer acidified to pH 2. The aqueous layer was back extractedwith EtOAc (4×100 ml), and the combined organics were dried over Na₂SO₄and the solvent was removed under reduced pressure after filtration. Theresidue was recrystallized from EtOAc/isooctane giving 1.7 g (90 %).C,₄H,₆F₂N₂O₄ requires C, 53.50 H, 5.13 N, 8.91. Anal found C, 53.30 H,5.26 N, 8.98.

Example D8 Synthesis of m-Nitrophenylacety1-L-alanine2,4,5-Trichlorophenyl Ester

[1089] m-Nitrophenylacetyl-L-alanine (1 eq.) and 2,4,5-tricholophenol(1.3 eq.) were stirred in dicholomethane. A 1.0 M solution of1,3-dicyclohexylcarbodiimide in dichloromethane (1.2 eq.) was added andthe mixture was stirred at ambient temperature for 16 hours. Theresulting mixture was filtered and the filtrate was concentrated underreduced pressure. The resulting oil was purified by silica gelchromatography using 1:2 ethyl acetate/hexanes as the eluant to providethe title compound as a pink solid. For C₁₇H₁₃Cl₃N₂O₅: Calc. 47.30% C,3.04% H, 6.49% N. Found 47.57% C, 3.18% H, 6.47% N.

Example D9 Synthesis of D,Lα-Methylphenylglycine Ethyl Ester

[1090] The title was prepared using the procedures described in J. J.Fitt and H. W. Gschwend, J. Org. Chem., 42, No. 15, 2639 (1977). Morespecifically, D,L-phenylglycine (Aldrich) was stirred indimethylformamide dimethylacetal and the mixture was heated at refluxunder an atmosphere of dry nitrogen for 4 hours. After cooling, themixture was concentrated under reduced pressure to provide a yellow oilysolid. The mixture was slurried in diethyl ether and filtered throughCelite. The filtrate was concentrated to an orange oil which waspurified by vacuum distillation to provide a yellow oil whichsolidified. The yellow solid was stirred in dry THF at −20 C under drynitrogen. Lithium bis(trimethylsilyl)amide (1.05 eq, 1.0M solution inTHF) was added dropwise. The resulting mixture was allowed to warm to−10 C. and stirring was continued for 1 hour at that temperature. Methyliodide (1.05 eq) was added and the mixture was allowed to warm ambienttemperature with stirring. After 14 hours, the mixture was concentrated.The residue was partitioned between aqueous potassium carbonate andchloroform. The organic portion was dried (sodium sulfate) andconcentrated under reduced pressure. The product was purified by silicagel chromatography to yield a yellow oil. The yellow oil was stirred inabsolute ethanol. Dry zinc chloride (4 eq.) was added and the mixturewas heated at reflux. After 14 hours, the mixture was concentrated underreduced pressure to provide a yellow oil. The oil was partitionedbetween aqueous potassium carbonate and chloroform. The organic portionwas dried (sodium sulfate) and concentrated under reduced pressure. Thetitle compound was purified by silica gel chromatography.

Example D10 Synthesis of D,L-Phthalimidoalanine Ethyl EsterHydrochloride

[1091] N-(Diphenylmethylene)glycine ethyl ester (1 eq.) (Aldrich) wasstirred in dry THF at −78° C. under an atmosphere of dry nitrogen.Lithium bis(trimethylsiyl)amide (1.02 eq, 1.0 M solution in THF) wasadded dropwise. The resulting mixture was stirred 1 hour at −78° C. ATHF solution of N-(bromomethyl)phthalimide (1.1 eq) (Aldrich) was addedand the mixture was allowed to warm to ambient temperature and thenstirring was continued for 1 hour. Hydrochloric acid (600 mL, 2N) wasadded and the mixture was stirred for 20 minutes. The THF was removed ona rotoevaporator. The resulting aqueous mixture was washed with diethylether, and then concentrated (to 100 mL) to yield a thick slurry. Awhite solid was collected, washed with cold water and dried in a vacuumoven to yield the title compound which was used without furtherpurification.

Example D11 Synthesis of N-(3-Nitrophenylacetyl)-L-alanine

[1092] The title compound was prepared by dissolving 9.27 g (0.0348mols) of the N-(3-nitrophenylacetyl)-L-alanine methyl ester in 60 mL ofdioxane and 15 mL of H₂O and adding LiOH (3.06 g, 0.0731 mol) that hasbeen dissolved in 15 mL of H₂O, After stirring for 4 hours, the dioxanewas removed under reduced pressure and the residue diluted with EtOAc,the layers were separated and the aqueous layer acidified to pH 2. Theaqueous layer was back extracted with EtOAc (4×100 ml), the combinedorganics were dried over Na₂SO₄ and the solvent was removed underreduced pressure after filtration. The residue was recrystallized fromEtOAc/isooctane giving 7.5 g (85 %). C₁₁H₁₂N₂O₅ requires C, 52.38 H,4.80 N, 11.11. Anal found C, 52.54 H, 4.85 N, 11.08. [α]₂₃=−29.9@589 nm.

Example D12 Synthesis of Methyl 2-Amino2-(3-fluorophenyl)acetateHydrochloride

[1093] Potassium cyanide (6.3, 0.1 mol) and ammonium carbonate (15.7 g,0.2 mol) were dissolved in 50 mL of water (in a well ventilated fumehood). 3- Fluorobenzaldehyde (5.0 g, 0.04 mol) was dissolved in 50 mL ofEtOH and added to the reaction. After stirring at reflux under nitrogenatmosphere for 17 hours, the reaction was cooled to 23° C., the pHadjusted to 2.0 by the addition of 5 N HCl and cooled to 5° C. Theresulting hydantoin was collected, rinsed with cold water and vacuumdried giving 3.59 of an off-white solid. The hydantoin was hydrolyzed atreflux using 1 N NaOH giving 2-amino-2-(3-fluorophenyl)acetic acid whichwas esterified via Procedure H in methanol to give the title compound.

Example D13 Synthesis of N-[N-(S)-2-Aminobutanoyl]-L-phenylglycinetert-Butyl ester

[1094] A mixture of N-[N-(benzyloxycarbonyl)-(S)-2-aminobutanoyl]-L-phenylglycine tert-butylester (4.13 g) (prepared from N-(benzyloxycarbonyl)-(S)-2-aminobutanoicacid (Novabiochem) and L-phenylglycine tert-butyl ester hydrochloride(Novabiochem) using General Procedure D) and 20% Pd(OH)₂/C (0.360 g) inEtOH (200 mL) was shaken in a Parr Apparatus under a hydrogen atmosphere(40 psi) for 4 hours. The solids were removed by filtration through aplug of Celite, while rinsing with EtOH. The filtrate was concentratedto an off-white oil, which was used without further purification. ¹H-NMRin CDCl₃ revealed that ˜10% trans-esterification to the ethyl occurredduring this reaction. The ethyl ester was removed by flashchromatography after subsequent reaction of this compound.

Example, D14 Synthesis of N-[N-L-Valinyl]-L-phenylglycine tert-Butylester

[1095] A mixture of N-[N-(benzyloxycarbonyl)-L-valinyl]-L-phenylglycinetert-butyl ester (4.63 g) (prepared from N-(benzyloxycarbonyl)-L-valine(Aldrich) and L-phenylglycine tert-butyl ester hydrochloride(Novabiochem) using General Procedure D) and 20% Pd(OH)2/C (0.360 g) inEtOH (200 mL) was shaken in a Parr Apparatus under a hydrogen atmosphere(40 psi) for 4 hours. The solids were removed by filtration through aplug of Celite, while rinsing with EtOH. The filtrate was concentratedto an off-white solid, which was used without further purification.¹H-NMR in CDCl₃ revealed that ˜1% trans-esterification to the ethyloccurred during this reaction. The ethyl ester was removed by flashchromatography after subsequent reaction of this compound.

Example D15 Synthesis of (S)-Phenylglycinol Methyl Ether

[1096] (S)-(+)-2-phenylglycinol (1 eq.) (Aldrich) was stirred in dry THFunder an atmosphere of dry nitrogen. Sodium hydride (1 eq.) was addedand the resulting mixture was stirred for 1 hour at ambient temperature.A THF solution of iodomethane (1 eq.) was added and the mixture wasstirred for 1 hour. The mixture was concentrated to provide a residuewhich was taken up in water and extracted with chloroform. The organicextracts were concentrated under reduced pressure to yield the titlecompound as an oil which was purified by silica gel chromatography toyield a crude product which was used without further purification.

Example D16 Synthesis of (S)-2-Hydroxy-2-methyl-1-phenylprop-1-ylamine

[1097] To a stirred, cooled (0° C.) suspension of 5.6 g (27.8 mmol) ofL-phenylglycine methyl ester hydrochloride (Aldrich) in 200 mL of dryTHF was added methylmagnesium bromide (46.3 mL, 138.9 mmol, 3.0 M indiethyl ether). During the addition, the internal temperature increasedto 24° C. Stirring was continued for 1 hour, after which the reactionwas carefully quenched by addition of saturated sodium bicarbonatesolution. The reaction mixture was partitioned between ethyl acetate andaqueous sodium bicarbonate solution, back extracting the aqueous layerwith 3 volumes of ethyl acetate. The combined organics were dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theproduct was purified by flash chromatography on silica gel, eluting with10% methanol in chloroform (neutralized with ammonium hydroxide) toafford 1.96 g to the title compound.

Example D17 Synthesis of 5Chloro-2-thiophenecarboxaldehyde

[1098] A solution of 2-chlorothiophene (Aldrich; 1 molar eq.) in THF wascooled to −78° C. and treated with n-butyllithium (1.6M in hexanes; 1.1molar eq.) in a dropwise manner. The resultant yellow solution wasstirred at −78° C. for 40 minutes. Dimethylformamide (1.1 molar eq.) wasadded dropwise and the reaction stirred and additional 30 minutes. Themixture was diluted with methylene chloride and washed with 10% aceticacid, 1 M potassium carbonate, and brine. The organic phase was driedover Na₂SO₄, filtered, and concentrated. The residue was purified byHPLC eluting with 15% ethyl acetate/hexanes to afford the titlecompound.

Example D18 Synthesis of (S)-(−)-α-Methylbenzylisocyanide

[1099] Prepared according to the general procedure of Wolber, E. K. A.;Ruchardt, C. Chem. Ber. 1991, 124, 1667. To a suspension of1,1′-carbonyldiimidazole (1.6 molar eq.; Aldrich) in acetonitrile at 0°C. was treated with methanesulfonic acid (3.2 molar eq.; Aldrich) in adropwise fashion. A very thick suspension results. S-(−)-α-Methylbenzylformamide (1 molar eq.; from Example D19 below) was added as a solutionin acetonitrile via cannulation. The mixture was stirred overnight atambient temperature. The suspension was filtered, washing withacetonitrile. The filtrate was concentrated and purified via flashchromatography eluting with 30% ethyl acetatelhexanes. The oil wasfurther purified via bulb-to-bulb distillation (80° C., 0.04 mm Hg)giving a pale yellow oil in 51% yield. Caled for C₉H₉N: C, 82.41; H,6.92; N, 10.68. Found: C, 82.56; H, 6.82; N, 10.71.

Example D19 Synthesis of (S)-(−)-α-Methylbenzyl formamide

[1100] (S)-(−)-α-Methylbenzylamine (1 molar eq.) was treated with ethylformate (80 molar eq.; Aldrich). A precipitate formed immediately. Thesuspension was heated to reflux (55° C.) for 3 hours. The precipitatewent into solution upon heating. The solution was cooled to ambienttemperature and concentrated via rotary evaporation. The resultant solidwas used without purification.

Example D20 Synthesis of 3-(Phenyl)benzaldehyde

[1101] A solution of 3-bromobiphenyl (Aldrich; 1 molar eq.) in dry THFwas cooled to −78° C. and treated with tert-butyllithium (Aldrich; 1.7 Min hexanes, 2 molar eq.) in a dropwise manner. The reaction was allowedto stir at −78° C. for 40 minutes. Dimethylformamide (Aldrich; 2.5 molareq.) was added and stirring continued an additional 20 minutes. Themixture was partitioned in a separatory funnel between methylenechloride and water. The organic layer was dried over Na₂SO₄, filtered,and concentrated. The residue was purified via HPLC eluting with 5 %ethyl acetate/hexanes. The desired aldehyde was obtained in 71 % yield.

Example D21 Synthesis of 4(Cyclohexyi)benzaidehyde

[1102] 18-Crown-6 (Aldrich; 4 molar eq.) and pyridinium chlorochromate(Aldrich; 4 molar eq.) were added together in chloroform and stirred for20 minutes. 4-Cyclohexylbenzylalcohol (from Example D22 below; 1 molareq.) was added and stirring continued for 3 hours. Ether was added andthe mixture filtered through a plug of silica eluting with ether. Thesolvent was removed via rotary evaporation. The residue was dissolved inether and washed with water. The organic layer was dried over Na₂SO₄,filtered, and concentrated.

Example D22 Synthesis of 4-(Cyclohexyl)benzyl Alcohol

[1103] To a solution of 4-cyclohexylbenzoic acid (Aldrich; 1 molar eq.)in toluene was added diiso-butylaluminum hydride (Aldrich; 1 M intoluene; 4 molar eq.) over a 2 hour period. After addition was complete,the reaction was heated to 60° C. for 1 hour. The reaction was cooled to5° C. and quenched with saturated aqueous ammonium chloride. The layerswe're separated and the aqueous layer extracted with ethyl acetate. Thecombined organics were filtered to remove salts and concentrated.

Example D23 Synthesis of 3,5-Difluorophenyl-α,α-difluoroacetic Acid

[1104] A solution of ethyl 3,5-difluorophenyl-α,α-difluoroacetate (fromExample D24 below; 1 molar eq.) in 50% aqueous ethanol was treated withlithium hydroxide (1.5 molar eq.). The solution was stirred for 3 hoursat ambient temperature then concentrated via rotary evaporation. Theresidue was taken up in water; a small amount of 1 N NaOH was added tomake basic. The aqueous mixture was extracted with ether. The aqueouslayer was acidified to pH 3 with 1 N HCl. The acid was extracted thricewith methylene chloride. The combined methylene chloride extracts weredried over Na₂SO₄, filtered, and concentrated.

Example D24 Synthesis of Ethyl 3,5-Difluorophenyl-α,α-difluoroacetate

[1105] Ethyl 3,5-difluorophenyl-α-ketoacetate (Rieke Metals, Inc.#14014; 1 molar eq.) was treated with (diethylamino)sulfur trifluoride(DAST) (2.5 molar eq.). The reaction was stirred at ambient for 72 hoursthen heated to 50° C. for 6 hours. The mixture was poured over ice andextracted with methylene chloride. The organic layer was washed withsaturated sodium bicarbonate, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified via HPLC eluting with 2% ethylacetate/hexanes.

Example D25 Synthesis ofN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine

[1106] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinemethyl ester (from Example 111 below) was hydrolyzed according toProcedure AF. The acid was recrystallized from isooctane/EtOAc providinga mixture of diastereomers at the phenylglycine center. Elementalanalysis; C₁₉H₁₈F₂N₄O₄ requires C, 60.63 H, 4.82 N, 7.44. Found; C,60.65 H, 5.02 N, 7.37. Mass spectroscopy (MH⁺377).

Example D26 Synthesis of 3-(4-Iodophenyl)propylarnine

[1107] N-(3-bromopropyl)phthalimide (1 eq., Aldrich) and 4-iodophenol (1eq., Aldrich) and potassium carbonate (2 eq.) was stirred inacetonitrile. The mixture was heated at reflux. After 64 hour, thereaction mixture was concentrated to a thick mixture which was slurriedin water. A white solid was collected, washed with water and vacuumdried.

[1108] The white solid was stirred in ethanol. Anhydrous hydrazine (2eq.) was added and mixture was heated at reflux for 18 hours. Thereaction mixture was concentrated to yield a solid which was treatedwith 1N NaOH and extracted with CHCl₃. The organic portion was dried,concentrated then diluted with ether. The mixture was treated with dryHCl. The title compound was collected as a white solid and vacuum dried.

Example D27 Synthesis of 2-Amino-1-phthalimidopentane Hydrochloride

[1109] 2-Amino-1-pentanol was stirred in a mixture of chloroform andsaturated aqueous sodium bicarbonate. Di-tert-butyl dicarbonate (1.05eq.) was added in one portion and the mixture was stirred until startingmaterial was consumed. The organic portion was separated, dried (sodiumsulfate) and concentrated. The crude material was purified by silica gelchromatrography using 1:1 ethyl acetate/hexanes.

[1110] The product was dissolved in THF. Triethylamine (1.1 eq.) wasadded and the mixture was cooled in an ice bath. Methanesulfonylchloride (1.1 eq.) was added dropwise and the mixture was stirred untilstarting material was consumed. The mixture was concentrated underreduced pressure then was partitioned between ethyl acetate and water.The organic portion was separated, dried (sodium sulfate) andconcentrated to yield a white solid which was chromatographed on silicagel using 30% ethyl acetate in hexanes and finally crystallized from1-chlorobutane/hexanes.

[1111] The crystalline product was stirred in dry DMF and potassiumphtalimide (1.1 eq.) was added. The mixture was stirred for 18 hoursthen was concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic portion wasdried and concentrated to yield a white solid. The solid was taken up inchloroform and filtered through a plug of silica. Eluent containingproduct was concentrated to yield the crude product as a white solid.

[1112] The white solid was taken up in dry dioxane and resultingsolution was saturated with gaseous HCl. After stirring for 30 minutes,the mixture was concentrated to yield a white solid which was trituratedin ether. The title compound was collected, washed with ether and driedin a vacuum oven.

Example D28 Synthesis of D,L-3,5-Difluorophenylglycine

[1113] KOH (11.76 grams), LiCi (2.95 grams), saturated aqueous ammonia(20 mL), and benzyltriethylammonium chloride (0.805 grams) were stirredand chilled in CH₂Cl₂ (17 mL). Gaseous ammonia was bubbled into thismixture with chilling (0° C.) to saturation. To the resulting mixturewas added 3,5-difluorobenzaldehyde (5.0 grams) (Lancaster) andchloroform (4.46 mL), dissolved in CH₂Cl₂ (17.5 mL) with concurrentsaturation with ammonia gas. The resulting mixture was stirred cold for4 hours and at 22.5° C. for 96 hours. Water (60 mL) and CH₂Cl₂ (20 mL)were added; the layers separated, and the aqueous layer was extracted 3times more with CH₂Cl₂. The aqueous layer was reduced in vacuo by 50%.The pH was adjusted to 6.5 with cold conc. HCl whereupon white crystalsof D,L-3,5 difluorophenylglycine formed (3.4343 grams).

Example D29 Synthesis of L3,5-Difluorophenylglycine Methyl Ester TartateSalt

[1114] 3.43 Grams of D,L-3,5 difluorophenylglycine (from Example D28above) was slurried in 50 mL methanol and 2.5 mL conc. H₂SO₄. Thereaction mixture was heated under gentle reflux for 18 hours. Themixture was chilled in and ice bath and the pH of the solution wasadjusted to 7.0 with saturated aqueous ammonia. The volatile organicsolvents were removed in vacuo and the aqueous portion was extractedthree times with CH₂Cl₂; the combined organic layers dried, filtered,and reduced in vacuo to provide 2.680 grams of crude ester. This ester,benzaldehyde (1.4085 grams), and (−) tartaric acid (1.9921 grams), weredissolved in 20.5 mL of hot ethanol and stirred slowly for 72 hours asthe title compound crystallized. The product was filtered and dried toprovide 3.4805 grams of the (−) tartarate salt.

Example D30 Synthesis ofN-(3,5-Difluorophenylacetyl)-L-3,5-difluorophenylglycine

[1115] L-3,5-Difluorophenylglycine (0.4291 g) (prepared fromL-3,5-difluorophenylglycine (−)-tartarate salt (from Example D29 above)by neutralization) and 3,5-difluoroacetic acid 0.367 gram were dissolvedin THF. EEDQ coupling using General Procedure AN afforded 0.7441 gramsof the title compound as the methyl ester. The ester was dissolved in1,4-dioxane (10 niL), chilled and LiOH.H₂O (89.0 mg) in water (10 mL)was added slowly and the mixture was stirred for 2 hours at 22.5° C.EtOAc (30 mL) and 1N HCl were added and the aqueous layer extracted twotimes. The combined organic layers were dried (MgSO₄) and reduced invacuo to provide the title compound (700.8 mg).

[1116] Each of the compounds set forth in the following examples wasprepared by one of the following general procedures, unless otherwiseindicated.

GENERAL PROCEDURE A EDC Coupling Procedure I

[1117] To a 1:1 mixture of the corresponding carboxylic acid and aminoester/amide in CH₂Cl₂ or DMF at 0° C. was added 1.5 equivalentstriethylamine, followed by 2.0 equivalents hydroxybenzotriazolemonohydrate, then 1.25 equivalents of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). Thereaction mixture was stirred overnight at room temperature and thentransferred to a separatory funnel. The mixture was washed with water,saturated aqueous NaHCO₃, 1 N aqueous hydrochloric acid, and saturatedaqueous sodium chloride, and then dried over MgSO₄. The solution wasstripped free of solvent on a rotary evaporator to yield the crudeproduct.

GENERAL PROCEDURE B EDC Coupling Procedure II

[1118] The carboxylic acid was dissolved in methylene chloride in around-bottomed flask. The amino acid (1 eq.), N-methylmorpholine (5 eq.)and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. Acooling bath was applied to the round-bottomed flask until the solutionreached 0°°. At that time, 1.2 eq. of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added.The solution was then allowed to stir overnight and come to roomtemperature under N₂ pressure. The reaction mixture was then washed withsaturated aqueous Na₂CO₃, 0.1 M citric acid, and brine before dryingwith Na₂SO₄ and removing the solvents to yield the crude product. Pureproducts were typically obtained byflash chromatography in anappropriate solvent.

GENERAL PROCEDURE C EDC Coupling Procedure III

[1119] A round-bottomed flask was charged with the appropriatecarboxylic acid (1.0 eq), hydroxybenzotriazole hydrate (1.1 eq) and theappropriate amine (1.0 eq) in THF under a nitrogen atmosphere. Anappropriate amount (1.1 eq. for the free amine and 2.2 eq. for aminehydrochloride salt) of a suitable base, such as Hunig's base was addedto the stirred mixture, followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.1eq). After stirring for about 4 h to 17 h at room temperature, thesolvent was removed at reduced pressure and the residue taken up inEtOAc (or a similar solvent)/H₂O. The extracts were washed withsaturated Na.HCO₃, 1 N aqueous hydrochloric acid, brine and dried overNa₂SO₄. In some cases, the isolated product required furtherpurification using standard procedures, such as chromatography and/orrecrystallisation.

GENERAL PROCEDURE D EDC Coupling Procedure IV

[1120] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at 0° C. was charged with THF, an amine or aminehydrochloride (1.0 eq.), carboxylic acid (1.1 eq.),1-hydroxybenzotriazole hydrate (1.15-1.2 eq), N,N-diisopropylethylamine(2.3 eq.), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC) (1. 15-1.2 eq.). The cooling bath was removed andthe mixture allowed to warm to room temperature with stirring for 10-20hours. The mixture was diluted with EtOAc and washed with 0.5 N aqueous.HCl (2×), dilute aqueous NaHCO₃ (1×), brine (1×) and dried over eitherNa₂SO₄ or MgSO₄. The drying agent was removed by filtration and thefiltrate concentrated in vacuo. The residue was either used withoutfurther purification or purified by standard procedures, such as flashchromatography on silica gel and/or recrystallization.

GENERAL PROCEDURE E EDC Coupling Procedure V

[1121] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at 0° C. or room temperature was charged withTHF, carboxylic acid (1.0 eq), an amine or amine hydrochloride (1.0-1.1eq.), 1-hydroxybenzotriazole hydrate (1.1-1.2 eq.),N,N-diisopropylethylamine (2.2-2.9 eq.), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)(1.1-1.2 eq.). The cooling bath was removed and the mixture allowed towarm to room temperature with stirring for 10-20 hours. The mixture wasdiluted with EtOAc and washed with 0.5 N aqueous HCl (2×), diluteaqueous NaHCO₃ (1×), brine (1×) and dried over either Na₂SO₄ or MgSO₄.The drying agent was removed by filtration and the filtrate concentratedin vacuo. The residue was either used without further purification orpurified using standard procedures, such as flash chromatography onsilica gel and/or recrystallization.

GENERAL PROCEDURE F EDC Coupling Procedure VI

[1122] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at 0° C. was charged with THF, carboxylic acid(1.0 eq.), an amine or amine hydrochloride (1.1 eq.),N,N-diisopropylethylamine (2.2-2.3 eq.), followed by1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)(1.1-1.2 eq.). The cooling bath was removed and the mixture allowed towarm to room temperature with stirring for 10-20 hours. The mixture wasdiluted with EtOAc and washed with 0.2 N aqueous HCl (2×), diluteaqueous NaHCO₃ (1×), brine (1×) and dried over either Na₂SO₄ or MgSO₄.The drying agent was removed by filtration and the filtrate concentratedin vacua. The residue was either used without further purification orpurified using standard procedures, such as flash chromatography onsilica gel and/or recrystallization.

GENERAL PROCEDURE G Methyl Ester Preparation

[1123] To 1-methyl-3-nitro-1-nitrosoguanidine (1.2 eq.) in diethyl ethercooled to 0° C. was added 40% KOH until bubbling ceased. This mixturewas then decanted into a plastic tube containing KOH pellets as a dryingagent. The solution was then added to the appropriate carboxylic acidand the mixture was stirred until the reaction was complete (asdetermined, for example, by tlc). The reaction was then quenched withacetic acid and extracted into EtOAc. Removal of the solvent affordedthe desired methyl ester.

GENERAL PROCEDURE H Carboxylic Acid Ester Preparation

[1124] To the appropriate amino acid or carboxylic acid in theappropriate alcohol was bubbled anhydrous HCL gas until the solution wassaturated. The reaction was stirred overnight at 25° C. and the solventwas then removed under reduced pressure. The residue was then dissolvedin EtOAc and this solution was washed with sodium bicarbonate solution.The organic layer were then dried over sodium sulfate, filtered andsolvent removed to afford the desired ester.

GENERAL PROCEDURE I tert-Butyl Ester Preparation I

[1125] To a solution of an N-CBZ-protected amino acid in CH₂Cl₂ wasadded 1.5 equivalents of N,N′-diisopropyl-O-t-butylisourea (prepared bystandard literature methods such as those found in Synthesis (1979), p.561), and the reaction was heated to reflux for 17 h. An additional 1.5equivalents of isourea were then added, and reflux was continued foranother 7 h. The reaction was then cooled to room temperature andfiltered through a bed of Celite 545, then stripped to dryness to leavea clear oil. The residue was dissolved in hexanes and filtered to removesolids, and the filtrate was washed with saturated aqueous NaHCO₃,water, saturated aqueous NaCl, and dried over MgSO₄. The solution wasconcentrated under reduced pressure to leave the product.

GENERAL PROCEDURE J tert-Butyl Ester Preparation II

[1126] The reaction was conducted in a sealed tube using the appropriatecarboxylic acid, a catalytic amount of H₂SO₄ (0.03 eq.) and an excess ofcondensed iso-butylene in dioxane or CH₂Cl₂ at −20° C. The reactiontimes varied from about 48 hours to about 120 hours. When the reactionwas complete, the solvent was removed under reduced pressure and theresidue dissolved in diethyl ether. This solution was washed with sodiumbicarbonate solution and the organic layer dried over sodium sulfate,filtered and solvent removed. The resulting product was purified usingstandard procedures, such as HPLC or titration using, for example,diethyl ether/hexanes.

GENERAL PROCEDURE K Amide Preparation I

[1127] To a solution of 3 equivalents of the desired amine in1,2-dichloroethane was added 5.2 equivalents triethylaluminumsubsurface. After stirring for 30 minutes at room temperature, asolution of the desired ester dissolved in 1,2-dichloroethane was added.The reaction was refluxed until tlc showed complete conversion,typically 3h. The reaction was then cooled to 0° C. and quenched with10% aqueous hydrochloric acid (Note: the acid should be added slowly assome foaming occurs during its addition). The mixture was transferred toa separatory funnel and the layers were separated. The aqueous phase waswashed with ethyl acetate, and the organic phases were washed withsaturated aqueous NaCl, dried over MgSO₄, and concentrated under reducedpressure to leave the crude product.

[1128] Alternatively, if the product is acid soluble, after the reactionis quenched, the reaction volume was reduced to about one-third of itsinitial volume under reduced pressure. To the resulting solution wasadded 20% aqueous potassium sodium tartrate (Rochelle's salt) and ethylacetate. The pH of the solution was then adjusted to −13, and thealuminum salts dissolved in the aqueous solution. The organic phase wasseparated, and the aqueous phase was extracted with ethyl acetate. Thecombined organic solution was washed with saturated aqueous NaCl, driedover MgSO₄, and concentrated under reduced pressure to leave the crudeproduct.

GENERAL PROCEDURE L Amide Preparation II

[1129] The carboxamide was prepared from its corresponding ester usingthe procedure described in Hogberg, T., et.al., J. Organic Chem., 1987,52, 2033-2036.

GENERAL PROCEDURE M Amide Preparation III

[1130] To the appropriate carboxylic acid (1.0 eq.) in THF was addedN-methylmorpholine (1.1 eq.) and the solution was cooled to −20° C. to0° C. iso-butyl chloroformate (1.1 to 2.1 eq.) was then added and thereaction mixture was stirred at −20° C. to 0° C. for 30 min. A mixtureof the appropriate amino acid, water and 1.5 eq. of potassium carbonatewas then added, and the resulting mixture was allowed to warm to roomtemperature and stir for 2 hrs. The reaction mixture was then pouredinto water and washed with EtOAc. The pH of the water layer was thenadjusted to 2.0 with 5 N HCl and the water layer was extracted withEtOAc. The combined organic layers were dried over sodium sulfate,filtered and the solvent removed under reduced pressure. The resultingcrude amide was used without further purification or purified usingstandard procedures such as chromatography or titration using, forexample, diethyl ether/hexanes or EtOAc/hexanes.

GENERAL PROCEDURE N Hydrolysis of Carboxylic Acid Esters

[1131] To the ester in a 1:1 mixture of CH₃OH/H₂O was added 2-5equivalents of K₂CO₃. The mixture was heated to 50° C. for 0.5-1.5 huntil tlcshowed complete reaction. The reaction was cooled to roomtemperature and the methanol was removed on a rotary evaporator. The pHof the remaining aqueous solution was adjusted to about 2, and ethylacetate was added to extract the product. The organic phase was thenwashed with saturated aqueous NaCl and dried over MgSO₄. The solutionwas stripped free of solvent on a rotary evaporator to yield theproduct.

GENERAL PROCEDURE O Removal of N-Carbobenzyloxy (CBZ) Protecting Groups

[1132] The N-CBZ-protected compound was dissolved in ethanol in ahydrogenation flask and a catalytic amount of 10% Pd/C was added. Themixture was hydrogenated at 20 psi H₂ on a Parr shaker for 30 min. Thereaction was then filtered through a pad of Celite 545 and stripped freeof solvent on a rotary evaporator to yield the product.

GENERAL PROCEDURE P Removal of the N-tert-Boc Protecting Group

[1133] The N-tert-Boc-amine was dissolved in a suitable dry solvent(such as 1,4-dioxane or ethyl acetate) and the solution was cooled in anice bath. Gaseous HCl was introduced into the solution until the mixturewas saturated with HCl. The mixture was then stirred until the reactionwas complete. The resulting mixture was concentrated under reducedpressure to yield the amine hydrochloride. The amine hydrochloride wasused without purification or was triturated using, for example, diethylether and the resulting solid was collected by filtration.

GENERAL PROCEDURE Q Halide Exchange (Finkelstein) Reaction

[1134] The corresponding alkyl bromide or alkyl chloride was dissolvedin 20 mL of methyl ethyl ketorne and 1 eq. of NaI was added. Thereaction was heated to 60° C. and stirred overnight. The cooled reactionmixture was extracted with dichloromethane (2×30 mL) and the combinedextracts were roto-evaporated at reduced pressure to give the crudeproduct. Pure products were typically obtained by flash chromatographyin an appropriate solvent.

GENERAL PROCEDURE R Oxime Reduction I

[1135] To the oxime ester in the alcohol corresponding to the ester wasadded formic acid (500 eq.) and water (500 eq.). The reaction mixturecooled to 5° C. and zinc dust (3.8 eq.) was added in portions over 20min. The reaction was then allowed to warm to room temperature andstirring was continued for 3 hours. The reaction was then filtered overHYFLO and the solvent removed under reduced pressure. The residue wasdissolved in EtOAc and this solution washed with saturated sodiumbicarbonate solution. The organic layer was then dried over sodiumsulfate, filtered and solvent removed to afford the product.

GENERAL PROCEDURE S Reduction of Esters to Alcohols

[1136] To a 0° C. solution of the starting ester in anhydrous THF wasadded 1.0 equivalents of LiBH₄ in THF. The reaction was stirred at roomtemperature overnight and then quenched with water. The THF was removedon a rotary evaporator and ethyl acetate was added. The phases wereseparated and the organic phase was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated underreduced pressure to afford the alcohol product.

GENERAL PROCEDURE T CDI Coupling Procedure

[1137] A solution of the appropriate acid (3.3 mmol) and1,1′-carbodiimidazole (CDI) in 20 mL THF was stirred for 2 h. The aminoacid ester hydrochloride (3.6 mmol) was added, followed by 1.5 mL (10.8mmol) of triethylamine. The reaction mixture was stirred overnight andthen dissolved in 100 mL of diethyl ether, washed with 10% HCl threetimes, brine once, 20% potassium carbonate once and brine once. Thesolution was dried over magnesium sulfate, filtered, and evaporated atreduced pressure to yield the product.

GENERAL PROCEDURE U EDC Coupling Procedure VII

[1138] A mixture of the appropriate carboxylic acid (1 eq.),1-hydroxybenzotriazole (1.6 eq.), the appropriate amine (1 eq.),N-methylmorpholine (3 eq.) and dichloromethane (or DMF for insolublesubstrates), cooled in an ice-water bath, was stirred until a clearsolution was obtained. EDC (1.3 eq.) was added to the reaction mixtureand the cooling bath was allowed to warm to ambient temperature over 1-2h. The reaction was then stirred overnight. The reaction mixture wasthen evaporated at reduced pressure to dryness under vacuum and 20%aqueous potassium carbonate was added to the residue. The mixture wasshaken vigorously and allowed to stand for hours or overnight, ifnecessary, until the oily product to solidify. The solidified productwas then filtered off, washed thoroughly with 20% potassium carbonate,water, 10% HCl, and water to give the product. No racemization wasobserved using this procedure.

GENERAL PROCEDURE V O-Acylation of Alcohols

[1139] To a solution of the alcohol (e.g.,N-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamidefrom Example 228 below) in pyridine was added 4 equivalents of aceticanhydride and the reaction was stirred at room temperature for 2.5 h.The reaction was quenched onto ice and then ethyl acetate was added andthe phases were separated. The organic phase was washed with 10% HCl,water, saturated aqueous NaCl, and dried over MgSO₄. The solution wasstripped free of solvent on a rotary evaporator to yield the product.

GENERAL PROCEDURE W O-Esterification of Alcohols

[1140] To a suspension of 0.95 equivalents of NaH in THF was added analcohol (e.g., N-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide fromExample 228 below) dissolved in THF. This solution was cooled to 0° C.,then 1.1 equivalents of an acyl chloride (e.g. trimethylacetyl chloride)was added. The reaction was stirred at room temperature overnight, thenwas quenched with water and ethyl acetate. The organic phase was washedwith water, saturated aqueous NaCl, and dried over MgSO₄. The solutionwas stripped free of solvent on a rotary evaporator to yield the crudeproduct.

GENERAL PROCEDURE X BOP Coupling Procedure

[1141] A solution of the carboxylic acid (1.0 eq.) and N-methylmorpholine (1.5 eq.) in dichloromethane was cooled to −20° C. undernitrogen. BOP (1.05 eq.) was added in one portion and the reactionmixture was maintained at −20° C. for 15 minutes. The appropriatealcohol (1.2 eq.) was added and the reaction mixture was allowed to warmto room temperature and stirring was continued for 12 hours. Thereaction mixture was then poured into water and extracted with ethylacetate (3×) and the combined organic layers were washed with saturatedaqueous citric acid (2×), saturated aqueous sodium bicarbonate (2×),brine (1×), and then rotoevaporated at reduced pressure to provide thecrude product.

GENERAL PROCEDURE Y BOC Removal Using TFA

[1142] The Boc-protected compound was added to a 1:1 mixture ofdichloromethane and trifluoroacetic acid (TFA) and the reaction mixturewas stirred until tlc indicated complete conversion, typically 2 hours.The solution was then stripped to dryness. The residue was suspended indichloromethane and again stripped to dryness to remove excess TFA. Theresidue was placed under high vacuum for several hours to afford thedesired TFA salt.

GENERAL PROCEDURE Z Amide Preparation IV

[1143] The trichlorophenyl ester (1 eq.) was stirred in DMF or THF andthe oxime or amine (1.2 eq.) was added. The mixture was stirred atambient temperature for 1-4 hours. In cases where the hydrochloride saltform of an amine was used, a suitable base such as diisopropylethylamine(1.2 eq.5 was also added. The resulting mixture was concentrated underreduced pressure to yield an oil or residue which was used withoutfurther purification or was purified by standard procedures, such assilica gel chromatography and/or recrystallization.

GENERAL PROCEDURE AA Sodium Borohydride Reduction

[1144] The ketone was dissolved in MeOH and treated with 1.0 equivalentof sodium borohydride. The reaction was stirred until tlcshowed thestarting material was consumed, typically 1 hour. The reaction mixturewas then evaporated at reduced pressure and chromatographed to affordthe alcohol product.

GENERAL PROCEDURE AB Preparation Amino Acid Derivatives Using ChiralAmines

[1145] (S)-(+)-α-Methylbenzyl amine was added dropwise to a solution of4-(phenyl)benzaldehyde (1 molar eq.) in THF followed by the addition of1.0 molar eqivalent of zinc chloride. The reaction mixture was allowedto stir at room temperature for 5 h. The cloudy mixture was then cooledto −30° C. and treated with tert-butylisocyanide (1.05 molar eq.). After20 minutes, N-(3,5-difluorophenylacetyl)-L-alanine was added andstirring was continued at −30° C. for 120 h. The reaction mixture wasthen poured into a seperatory funnel and diluted with CH₂Cl₂, washedwith sodium bicarbonate. The organic layer was then washed with 0.5 NHCl, followed by brine. The organic layer was then dried over Na₂SO₄,filtered and concentrated to giveN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N′-(S)-α-methylbenzyl-2-amino-2-(4-phenylphenyl)acetamide,as a mixture of isomers. At this stage, the isomers were typicallyseparated by HPLC chromatography using, for example, a gradient of 30 to35% EtOAc/hexanes. The ci-methylbenzyl protecting group was then removedfrom the S,S isomer by added 10 molar equivalents of triethylsilane and20 molar equivalents of trifluoroacetic acid to the S,S isomer. Thereaction was then heated to 37° C. for 3 h and then poured into ethylacetate and washed with sodium bicarbonate. The organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified byrecrystallisation from ethyl acetate or ethyl acetate/hexanes. Variousother aldehydes and carboxylic acids can be used in this procedure toprovide for a variety of compounds useful in this invention.

GENERAL PROCEDURE AC Oxime Reduction II

[1146] To a solution of the oxime ester in the alcohol corresponding tothe ester was added a catalytic amount of acetic acid and 0.1 moleequivalent of 10% Pd/C. The reaction vessel (Parr shaker) was chargedwith hydrogen to 40 PSI and this mixture was shaken for 3 h. Thereaction mixture was then filtered over HyFlo and concentrated. Theresidue was dissolved in ethyl acetate and washed with a saturatedsolution of sodium bicarbonate. The organic layer was then dried overNa₂SO₄, filtered and concentrated to give the desired amine.

GENERAL PROCEDURE AD Mitsunobu Reaction

[1147] To a solution ofN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester in20 mL of THF was added 1.3 equivalents each of triphenylphosphine anddiethyl azodicarboxylate (DEAD), and 1.0 equivalents of an alcohol. Themixture was stirred a room temperature overnight and the solvent wasthen removed. The residue was purified by standard procedures, such aschromatography and/or recrystallization.

GENERAL PROCEDURE AE O-Alkylation of Tyrosine Derivatives

[1148] To a solution ofN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester in20 mL of acetone was added 1.3 equivalents of an alkyl bromide and 3.0equivalents of potassium carbonate as a fine powder and a catalyticamount of sodium iodide. The reaction mixture was stirred at roomtemperature overnight and then partitioned between DCM and water. Theorganic layer was dried over anhydrous sodium sulfate, stripped ofsolvents and purified using standard procedures, such as chromatographyand/or recrystallization.

GENERAL PROCEDURE AF Hydrolysis of Carboxylic Acid Esters

[1149] A solution of the carboxylic acid ester (1.0 eq.) and lithiumhydroxide (1.1 eq.) in 1:2 water/dioxane was stirred at 23° C. for 1hour. The reaction mixture was then acidified to pH 3 with 1 N HCl andextracted with ethyl acetate. Concentration of the ethyl acetateextracts provided the product. In some cases, the product was furtherpurified using standard procedures, such as chromatography and/orrecrystallization.

GENERAL PROCEDURE AG Methyl Ester Formation from Amino Acids

[1150] The amino acid (amino acid or amino acid hydrochloride) issuspended in methanol and chilled to 0° C. HCl gas is bubbled throughthis solution for 5 minutes. The reaction is allowed to warm to roomtemperature then stirred for 4 hours. The solvents are then removed toafford the desired amino acid methyl ester hydrochloride. This productis usually used without further purification.

GENERAL PROCEDURE AH EEDO Coupling Procedure

[1151] A round bottom flask containing a magnetic stir bar under asatmosphere of nitrogen at room temperature was charged with THF, thecarboxylic acid (1 eq.), the amine hydrochloride (1. 1 eq.) and EEDQ(1.1 eq.) and the reaction mixture was allowed to stir for 15 minutes.4-Methylmorpholine (1.1 eq.) was added to the reaction and stirring wascontinued at room temperature for 15-20 hours. The reaction mixture wasthen concentrated in vacuo and the resulting residue was partitionedbetween ethyl acetate and water. The organic phase was separated andwashed with saturated aq. NH₄Cl (2×), saturated aq. NaHCO₃ (2×),followed by brine (1×). Organic phase dried over Na₂SO₄. The dryingagent was removed by filtration and the filtrate concentrated in vacuo.The residue was either used without further purification or purifiedusing standard procedures, such as flash chromatography on silica geland/or recrystallization.

GENERAL PROCEDURE AI N-tert-BOC Protection of Amino Acids

[1152] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at room temperature was charged with dioxane,water, 1.0 N aq. sodium hydroxide, and the amino acid (1 eq). Stirringwas initiated and the flask was cooled in an ice bath.Di-t-butyldicarbonate (1.1 eq) was added to the reaction mixture,followed by removal of the ice bath and slow warming to room temperatureover 1 hour. The reaction was partially concentrated on the rotaryevaporator followed by the addition of ethyl acetate. The flask wasre-cooled in an ice bath and the mixture was acidified to a pH of 2-3through the addition of potassium bisulfate. The reaction wastransferred into a seperatory funnel and the organic layer wasseparated. The aqueous layer was extracted with ethyl acetate and thecombined organic layers were dried over Na₂SO₄. The drying agent wasremoved by filtration and the filtrate concentrated in vacuo. The solidwas used without further purification.

GENERAL PROCEDURE AJ Removal of N-Carbobenzyloxy (CBZ) Protecting Groups

[1153] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at room temperature was charged with methanol,tetrahydrofuran, 20% Pd(OH)₂/C (1 mass eq.), and the CBZ-protecteddipeptide. Stirring was initiated and the flask was purged (3×) withhydrogen. The reaction mixture was allowed to stir at room temperatureovernight under an atmosphere of hydrogen. The reaction was filtered andthe filtrate was concentrated in vacuo. The resulting solid was used asis or purified via silica gel chromatography.

GENERAL PROCEDURE AK Addition of N-Carbobenzyloxy (CBZ) ProtectingGroups

[1154] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at room temperature was charged with water,sodium carbonate (2.2 eq.), and amino acid (1.0 eq.). The slurry wasstirred at room temperature for 1 hour. Benzylchloroformate was added tothe reaction and stirring was continued overnight. The reaction mixturewas extracted with CH₂Cl₂ (3×) and the combined organic extracts wereacidified to a pH of 2-3. The resulting solid was isolated via vacuumfiltration.

GENERAL PROCEDURE AL Preparation of Amino Acid Derivatives Using ChiralAmines II

[1155] A solution of aryl aldehyde (1 molar eq.) in THF was treated withS-(−)-α-methylbenzylamine (1 molar eq.), followed by MgSO₄. The reactionmixture was stirred for 1 hour then treated with tert-butylisocyanide(1.5-2.0 molar eq.) and N-(3,5-difluorophenylacetyl)-L-alanine (1.5-2.0molar eq.). The reaction was allowed to stir for 60 hours. The reactionwas diluted with methylene chloride and washed with 0.01 N HCl andsaturated aqueous NaHCO₃. Each aqueous wash was back-extracted withmethylene chloride. The combined organics were washed with brine, driedover Na₂SO₄, filtered and concentrated to giveN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N′-R-α-methylbenzyl-2-amino-2-DL-(aryl)acetamide.At this stage, the isomers were separated if possible by HPLCchromatography using, for example, a gradient of 20 to 25% ethylacetate/hexanes. The ci-methylbenzyl protecting group was then removedfrom the peptide by adding 10 molar equivalents of triethylsilane and 20molar equivalents of trifluoroacetic acid to the compound. The reactionwas heated to 37° C. for 3 hours and then poured into ethyl acetate andwashed with sodium bicarbonate. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by trituration withether or ether/hexanes. Various other aldehydes, isocyanides, andcarboxylic acid can be used in this procedure to provide for a varietyof compounds useful in this invention.

GENERAL PROCEDURE AM Preparation of Amino Acid Derivatives Using ChiralAmines III

[1156] A solution of an aromatic aldehyde (3 molar eq.) andS-(α)-α-methylbenzylamine (1 molar eq.) in methanol was treated withtitanium(IV) isopropoxide (1.5 molar eq.). After stirring the mixture atambient temperature for 6 hours, tert-butylisocyanide (1.1 molar eq.)was added followed by N-(3,5- difluorophenylacetyl)-L-alanine (1.2 molareq.) 40 minutes later. The reaction mixture was stirred for 72 hours.The methanol was removed via rotary evaporation. The residue wasdissolved in methylene chloride and washed with 0.01 N HCl. The emulsionwas filtered through celite washing with methylene chloride. The layerswere separated; the organic phase was washed with saturated NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to give N-tertbutyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N′-R-α-methylbenzyl-2-amino-2-DL-(aryl)acetamide.At this stage the isomers were separated if possible by HPLCchromatography using, for example, a gradient of 20 to 25% ethylacetate/hexanes. The α-methylbenzyl protecting group was then removedfrom the peptide by adding 10 molar equivalents of triethylsilane and 20molar equivalents of trifluoroacetic acid to the compound. The reactionwas heated to 37° C. for 3 hours and then poured into ethyl acetate andwashed with sodium bicarbonate. The organic layer was dried over Na₂SO₄,filtered, and concentrated. The residue was purified by trituration withether or ether/hexanes. Various other aldehydes, isocyanides, andcarboxylic acid can be used in this procedure to provide for a varietyof compounds useful in this invention.

GENERAL PROCEDURE AN EEDO Coupling Procedure II

[1157] To a 1:1 mixture of the corresponding carboxylic acid and aminoester/amide in THF at 0° C. was added 1.1 equivalents of EEDQ. Thereaction mixture was stirred for 18 hours at 22.5° C. The solvent wasremoved under reduced pressure or under a stream of nitrogen and theresidue dissolved in EtOAc. The organic solution was washed 1 time withsaturated NaHCO₃ solution, 1 time with N HCl, and dried over MgSO₄. Theorganic solution was reduced in vacuo to yield the product.

GENERAL PROCEDURE AO Preparation of Primary Amides

[1158] A sealable pressure tube containing a magnetic stir bar under anatmosphere of nitrogen at room temperature was charged with a methylester (1 eq.), sodium cyanide (0.1 eq.) and a 7M solution of ammonia inmethanol. The tube was sealed and heated to 45° C. with stirring for 18hours. The reaction was allowed to cool to room temperature and theresulting precipitate was isolated by vacuum filtration. The solid waseither washed with methanol or recrystallyzed from ethylacetate/methanol.

EXAMPLE 1 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-Lalaninyl]-(S)-2-aminohexanoate

[1159] Following General Procedure A (without the 1N HCl wash) and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and norleucinemethyl ester hydrochloride (Sigma), the title compound was prepared as asolid (mp=142-143° C.). The reaction was monitored by tlc (Rf=0.71 in10% CH₃OH/CH₂Cl₂, 0.22 in 50% EtOAc/hexanes) and the product waspurified by silica plug chromatography using CH₂Cl₂ as the eluent.

[1160] NMR data was as follows:

[1161]¹H-nmr (CDCl₃): δ=6.90 (d, J=7.69 Hz, 1H), 6.80 (m, 3H), 6.70 (m,1H), 4.62 (quint, J=7.2 Hz, 1H), 4.48 (m, 1H), 3.72 (s, 3H), 3.51 (s,2H), 1.78 (m, 1H), 1.60 (m, 1H), 1.36 (d, J=7.02 Hz, 3H), 1.25 (m, 4H),0.85 (m, 3H).

[1162]¹³C-nmr (CDCl₃): δ=173.23, 172.69, 169.97, 165.30, 165.12, 162.00,139.01, 138.88, 138.76, 112.93, 112.83, 112.70, 112.60, 103.63, 103.30,102.97, 52.94, 49.38, 43.28, 32.32, 27.95, 22.75, 19.23, 14.35.

[1163] C₁₈H₂₄F₂N₂O₄ (MW=370.40); mass spectroscopy (MH⁺) 371.

EXAMPLE 2 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-histidine Methyl Ester

[1164] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and L-histidinemethyl ester dihydrochloride (Sigma), the title compound was prepared asa solid (mp=195-197° C.). The reaction was monitored by tlc (Rf=0.29 in10% CH₃OH/CH₂Cl₂).

[1165] NMR data was as follows:

[1166]¹H-nmr (CD₃OD): δ=7.60 (s, 1H), 7.00-6.81 (m, 4H), 4.70 (t, 1H),4.39 (q, 1H), 3.72 (s, 3H), 3.60 (s, 2H), 3.22-3.00 (m, 2H), 1.38 (d,3H).

[1167]¹³C-nmr (CD₃OD): δ=175.46, 172.56, 172.94, 166.64, 166.47, 163.38,163.20, 141.73, 141.60, 141.47, 136.85, 113.92, 113.82, 113.70, 113.59,103.89, 103.55, 103.21, 54.55, 53.31, 51.00, 43.21, 43.19, 30.36, 18.44.

[1168] C₁₈H₂₀F₂N₄O₄ (MW=394.38); mass spectroscopy (MH⁺) 395.

EXAMPLE 3 Synthesis ofN-Benzyl-N′-[N-(3,5-difluorophenylacetyl)-alaninyl]-(S)-2-aminohexanamide

[1169] Following General Procedure K and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (fromExample 1 above) and benzylamine (Aldrich), the title compound wasprepared as a solid (mp=>200° C). The reaction was monitored by tlc(Rf=0.29 in 5% CH₃OH/CH₂Cl₂) and the product was purified by preparativeplate chromatography.

[1170] NMR data was as follows:

[1171]¹H-nmr (CDCl₃): δ=7.05 (m,5H), 6.65 (m, 3H), 4.10 (m, 4H), 3.35(d, 2H), 1.35 (m, 9H), 0.65 (m, 3H).

[1172]¹³C-nmr (CDCl₃): δ=175.48, 174.75, 173.16, 166.64, 166.46, 163.37,141.55, 141.42, 140.38, 130.04, 129.95, 129.05, 128.95, 128.73, 113.94,113.83, 113.71, 113.60, 103.90, 103.88, 103.56, 103.22, 55.43, 51.26,44.53, 43.21, 33.38, 29.56, 23.91, 18.28, 14.78.

[1173] C₂₄H₂₉F₂N₃O₃ (MW=445.51); mass spectroscopy (MH⁺) 446.

EXAMPLE 4 Synthesis ofN-2-(N,N-Dimethylamino)ethyl-N′-[N-(3,5difuorophenylacetyl)-Lalaninyl]-(S)-2-aminohexanamide

[1174] Following General Procedure K and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (fromExample 1 above) and N,N-dimethylethylenediamine (Aldrich), the titlecompound was prepared as a solid (mp=182-187° C.). The reaction wasmonitored by tlc (Rf=0.51 in 15 % CH₃OH/CH₂Cl₂) and the product waspurified by preparative plate chromatography using 15% CH₃OH/CH₂Cl₂ asthe eluent.

[1175] NMR data was as follows:

[1176]¹H-nmr (CDCl₃): δ=7.21 (d, 1H), 6.80 (m, 5H), 4.64 (m, 1H), 4.48(q, 1H), 3.57 (s, 2H), 3.30 (q, 2H), 2.41 (t, 2H), 2.22 (s, 6H), 1.70(m, 2H), 1.32 (m, 7H), 0.87 (m, 3H).

[1177]¹³C-nmr (CDCl₃): δ=172.2, 172.0, 170.0, 165.4, 165.3, 163.9,162.1, 162.0, 139.1, 138.8, 113.1, 112.8, 103.6, 103.3, 103.0, 58.1,54.0, 49.7, 45.7, 43.3, 38.1, 33.2, 28.2, 23.0, 19.2, 14.4.

[1178] C₂₁H₃₂F₂N₄O₃ (MW=426.51); mass spectroscopy (MH⁺) 427.

EXAMPLE 5 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amninohexanamide

[1179] Following General Procedure K and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (fromExample 1 above) and 2-methoxyethylamine (Aldrich), the title compoundwas prepared as a solid (mp=>200° C.). The reaction was monitored by tlc(Rf=0.42 in 10% CH₃OH/CH₂Cl₂) and the product was purified by flashchromatography using 12% CH₃OH/CH₂Cl₂ as the eluent.

[1180] NMR data was as follows:

[1181]¹H-nmr (CDCl₃): δ=7.85 (bd, J=8.79 Hz, 0.5H), 7.64 (bd, J=7.81 Hz,0.5H), 7.35 (m, 1H), 7.16 (bd, J=7.27 Hz, 0.5H), 7.06 (bs, 0.5H), 6.83(m, 2H), 6.68 (m, 1H), 4.70 (m, 2H), 3.56 (d, J=9.89 Hz, 2H), 3.40 (m,7H), 1.57 (m, 10H), 0.84 (m, 3H).

[1182]¹³C-nmr (CDCl₃): δ=172.62, 172.58, 172.14, 172.04, 170.02, 169.91,165.33, 165.15, 162.08, 112.99, 112.92, 112.82, 112.77, 112.66, 112.59,103.54, 103.34, 103.31, 103.29, 71.46, 71.44, 59.27, 59.24, 53.76,49.64, 49.43, 43.29, 39.79, 33.26, 33.22, 28.10, 28.03, 22.97, 22.91,19.71, 19.61, 19.56, 19.51, 14.46, 14.43.

[1183] C₂₀H₂₉F₂N₃O₄ (MW=413.47); mass spectroscopy (MH⁺) 414.

EXAMPLE 6 Synthesis ofN-2-(N,N-Dixnethylainino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1184] Following General Procedure K and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester(from Example 94 below) and N,N-dimethylethylenediamine (Aldrich), thetitle compound was prepared as a solid (mp=174-182° C.). The reactionwas monitored by tlc (Rf=0.31 in 10% CH₃OH/CH₂Cl₂) and the product waspurified by preparative plate chromatography using 10% CH₃OH/CH₂Cl₂ asthe eluent.

[1185] NMR data was as follows:

[1186]¹H-nmr (CD₃OD): δ=7.22 (m, 5h), 6.85 (m, 3H), 4.51 (m, 1H), 4.18(m, 1H), 3.57 (m, 2H), 3.50-2.45 (m, 6H), 2.39 (s, 6H), 1.26 (d, 2.4H),1.10 (d, 0.66H).

[1187]¹³C-nmr (CD₃OD): δ=176.03, 175.50, 174.20, 173.99, 173.50, 173.22,166.63, 166.46, 163.36, 163.19, 141.65, 141.52, 141.39, 139.38, 139.00,130.90, 130.74, 130.05, 130.01, 128.37, 128.30, 114.03, 113.93, 113.80,113.70, 103.96, 103.62, 103.57, 103.28, 59.18, 59.14, 56.78, 56.51,51.93, 51.74, 45.53, 45.47, 43.21, 43.18, 42.92, 38.84, 38.65, 37.94,37.85, 18.09, 17.73.

[1188] C₂₄H₃₀F₂N₄O₃ (MW=460.53); mass spectroscopy (MH⁺) 461.

EXAMPLE 7 Synthesis ofN-(4Pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1189] Following General Procedure K and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester(from Example 94 below) and 4-(aminomethyl)pyridine (Aldrich), the titlecompound was prepared as a solid (mp=>200° C.). The reaction wasmonitored by tlc (Rf=0.46 in 10% CH₃OH/CH₂Cl₂) and the product waspurified by recrystallization from ethyl acetate.

[1190] NMR data was as follows:

[1191]¹H-nmr (CD₃OD): δ=8.37 (d, 2H), 7.25 (m, 5H), 7.11 (d, 2H), 6.85(m, 3H), 4.56 (t, 1H), 4.29 (m, 3H), 3.64 (s, 2H), 3.08 (m, 2H), 1.30(d, 3H).

[1192]¹³C-nmr (CD₃OD): δ=175.46, 174.04, 173.26, 166.60, 166.43, 163.34,163.16, 150.97, 150.44, 141.59, 141.45, 138.84, 130.95, 130.13, 128.44,124.28, 113.98, 113.87, 113.75, 113.64, 103.91, 103.57, 103.23, 62.08,57.01, 43.33, 43.12, 38.93, 21.41, 18.16, 15.02.

[1193] C₂₆H₂₆F₂N₄O₃ (MW=480.52); mass spectroscopy (MH⁺) 481.

EXAMPLE 8 Synthesis ofN-(3-Pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylaianinamide

[1194] Following General Procedure K and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester(from Example 94 below) and 4-(aminomethyl)pyridine (Aldrich), the titlecompound was prepared as a solid (mp=199-210° C.). The reaction wasmonitored by tlc (Rf=0.46 in 10% CH₃OH/CH₂Cl₂, minor isomer Rf=0.50) andthe product was purified by preparative plate chromatography using 10%CH₃OH/CH₂Cl₂ as the eluent.

[1195] NMR data was as follows:

[1196]¹H-nmr (CD₃OD): δ=8.42 (m, 2H), 7.61 (m, 1H), 7.29 (m, 6H), 6.90(m, 3H), 4.61 (m, 1H), 4.33 (m, 3H), 3.58 (s, 1.5H), 3.54 (s, 0.5H),3.10 (m, 2H), 1.33 (d, 2.25H), 1.15 (d, 0.75H).

[1197]¹³C-nmr (CD₃OD): δ=176.00, 175.34, 174.03, 173.81, 173.23, 166.61,166.44, 163.35, 163.17, 149.93, 149.20, 141.48, 139.20, 138.72, 138.10,138.03, 136.88, 136.79, 130.89, 130.70, 130.06, 130.02, 128.40, 128.33,125.71, 113.97, 113.87, 113.74, 113.64, 103.92, 103.58, 103.53, 103.23,56.88, 56.66, 55.74, 53.21, 43.22, 43.15, 42.89, 42.06, 41.98, 39.04,38.88, 38.77, 18.18, 17.79.

[1198] C₂₆H₂₆F₂N₄O₃ (MW=480.52); mass spectroscopy (MH⁺) 481.

EXAMPLE 9 Synthesis ofN-(4-Pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)L-alaninyl]-(S)-2-aminohexanamide

[1199] Following General Procedure K and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (fromExample 1 above) and 4-(aminomethyl)pyridine (Aldrich), the titlecompound was prepared as a solid (mp=181-205° C.). The reaction wasmonitored by tlc (Rf=0.51 in 10% CH₃OH/CH₂Cl₂) and the product waspurified by preparative plate chromatography using 10% CH₃OH/CH₂Cl₂ asthe eluent.

[1200] NMR data was as follows:

[1201]¹H-nmr (CD₃OD): β=8.48 (m, 0.8H), 8.42 (m, 1.2H), 7.37 (d, J=6.10,0.8H), 7.28 (d, J=6.11, 1.2H), 6.85 (m, 3H), 4.39 (m, 4H), 3.61 (s,0.8H), 3.53 (d, J=2.99, 1.2H), 2.05-1.25 (m, 9H), 0.90 (m, 3H).

[1202]¹³C-nmr (CD₃OD): δ=176.61, 175.71, 175.33, 175.29, 173.32, 173.24,166.49, 166.32, 163.22, 163.05, 151.30, 151.24, 150.55, 150.41, 141.54,141.41, 124.35, 124.20, 113.95, 113.85, 113.72, 113.62, 103.86, 103.57,103.52, 103.18, 55.72, 55.64, 51.98, 43.38, 43.19, 42.82, 33.07, 32.57,29.87, 29.67, 23.90, 23.82, 18.24, 17.86, 14.80.

[1203] C₂₃H₂₈F₂N₄O₃ (MW=446.50); mass spectroscopy (MH⁺) 447.

EXAMPLE 10 Synthesis of teit-butylN-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate

[1204] Step A—t-Butyl Ester Formation

[1205] To a solution of Z-norleucine-OH in CH₂Cl₂ was added 1.5equivalents of N,N′-diisopropyl-O-t-butylisourea (prepared by the methodof Synthesis (1979) p.561 for review) and the reaction was heated toreflux for 17 hours. An additional 1.5 equivalents of isourea was thenadded, and reflux was continued for another 7 hours. The reaction wasthen cooled to room temperature and filtered through a bed of Celite545, then stripped to dryness to leave a clear oil. The residue wasdissolved in hexanes and filtered to remove solids, and the filtrate waswashed with saturated aqueous NaHCOj, water, saturated aqueous NaCl, anddried over MgSO₄. The solution was concentrated under reduced pressureto leave the product.

[1206] Step B—CBZ Removal

[1207] The CBZ-protected amino ester was dissolved in ethanol in ahydrogenation flask and a catalytic amount of 10% Pd/C was added. Themixture was hydrogenated at 20 psi H₂ on a Parr shaker for 30 min. Thereaction was then filtered through a pad of Celite 545 and stripped freeof solvent on a rotary evaporator to yield the product, norleucinetert-butyl ester hydrochloride.

[1208] Step C

[1209] Following General Procedure D and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and thenorleucine tert-butyl ester hydrochloride, the title compound wasprepared as a semi-solid. The reaction was monitored by tlc (Rf=0.41 in50% EtOAc/hexanes) and the product was purified by flash chromatographyusing 50% EtOAc/hexanes as the eluent, followed by preparative platechromatography using 50% EtOAc/hexanes as the eluent.

[1210] NMR data was as follows:

[1211]¹H-nmr (CDCl₃): δ=7.63 (d, J=7.7 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H),6.8 (m, 2H), 6.7 (m, 1H), 4.8 (m, 1H), 4.36 (q, J=5.6 Hz, 1H), 3.52 (s,2H), 1.8-1.1 (m, 15H), 0.8 (m, 3H).

[1212]¹³C-nmr (CDCl₃): δ=173.0, 171.8, 170.2, 165.1, 165.0, 161.9,161.7, 139.6, 139.4, 139.3, 112.8, 112.7, 112.6, 112.5, 103.2, 102.9,102.6, 82.3, 53.6, 49.3, 43.0, 32.2, 28.4, 27.8, 22.7, 19.4, 14.7, 14.2.

[1213] C₂₁H₃₀F₂N₂O₄ (MW=412.48); mass spectroscopy (MH⁺) 413.

EXAMPLE 11 Synthesis of N-[N-(Pent-4enoyl)-L-alaninyl]-L-phenylalanineMethyl Ester

[1214] Following General Procedure A and usingN-(L-alaninyl)-L-phenylalanine methyl ester (prepared by couplingN-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) usingGeneral Procedure A, followed by removal of the BOC-group using GeneralProcedure Y) and pent-4-enoic acid (Aldrich), the title compound wasprepared as a solid (mp=125.5-126.5° C.). The reaction was monitored bytlc (Rf=0.32 in 50% EtOAc/hexanes; 0.51 in 10% CH₃OH/CH₂Cl₂) and theproduct was purified by flash chromatography using 10% CH₃OH/CH₂Cl₂ asthe eluent.

[1215] NMR data was as follows:

[1216]¹H-nmr (CDCl₃): δ=7.27 (bd, J=7.82 Hz, 1H), 7.25-7.05 (m, 5H),6.72 (bd, J=7.57 Hz, 1H), 5.75 (m, 1H), 4.96 (m, 2H), 4.59 (quint, J=7.2Hz, 1H), 3.65 (s, 3H), 3.05 (m, 4H), 2.40-2.18 (m, 4H), 1.28 (d, J=7.02Hz, 3H).

[1217]¹³C-nmr (CDCl₃): δ=173.06, 172.77, 172.36, 137.47, 136.53, 129.76,129.07, 116.09, 54.10, 52.87, 49.06, 38.31, 25.93, 30.03, 19.17.

[1218] C₁₈H₂₄N₂O₄ (MW=332.40); mass spectroscopy (MNa+) 355.0.

EXAMPLE 12 Synthesis of N-[N-(Dec-4-enoyl)-L-alaninyl]-L-phenylalanineMethyl Ester

[1219] Following General Procedure A and usingN-(L-alaninyl)-L-phenylalanine methyl ester (prepared by couplingN-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester (Sigma) usingGeneral Procedure A, followed by removal of the BOC-group using GeneralProcedure Y) and dec-4-enoic acid (prepare from ethyl dec-4-enoate (ICM)using General Procedure N), the title compound was prepared as a solid(mp=115.5-117.5° C.). The reaction was monitored by tlc (Rf=0.52 in 50%EtOAc/hexanes; 0.60 in 10% CH₃OH/CH₂Cl₂) and the product was purified byflash chromatography using 10% CH₃OH/CH₂Cl₂ as the eluent.

[1220] NMR data was as follows:

[1221]¹H-nmr (CDCl₃): δ=7.54 (bd, J=7.69 Hz, 1H), 7.22-7.04 (m, 5H),6.91 (bd, J=7.69 Hz, 1H), 5.37 (m, 2H), 4.73 (q, J=6.9 Hz, 1H), 4.63(quint, J=7.2 Hz, 1H), 3.61 (s, 3H), 3.02 (m, 2H), 2.40-2.10 (m, 4H),1.89 (m, 2H), 1.35-1.13 (m, 9H), 0.82 (m, 3H).

[1222]¹³C-nmr (CDCl₃): δ=173.26, 173.05, 172.38, 136.65, 132.30, 129.74,128.99, 128.68, 127.48, 54.19, 52.74, 48.97, 38.28, 36.70, 33.04, 31.93,29.68, 29.09, 23.06, 19.23, 14.61.

[1223] C₂₃H₃₄N₂O₄ (MW=402.54); mass spectroscopy (MNa⁺) 425.0.

EXAMPLE 13 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dirnethylamino)propoxy]phenylalanineMethyl Ester

[1224] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) andL-4-[3-(N,N-dimethylamino)propoxy]-phenylalanine methyl ester (preparedfrom N-BOC-L-tyrosine methyl ester (Bachem) and3-dimethylamino-1-propanol (Aldrich) using a Mitsunobu procedureessentially as described in General Procedure AD, followed by removal ofthe BOC-group using General Procedure Y), the title compound wasprepared as a solid (mp=153-155° C.). The reaction was monitored by tlc(Rf =0.36 in 10% MeOH/DCM/1% TEA) and the product was purified byacid/base washes.

[1225] NMR data was as follows:

[1226]¹H-nmr (CDCl₃): δ=6.973-6.947 (d, 2H); 6.794-6.766 (d, 2H);6.743-6.714 (d, 2H); 6.735-6.676 (t, 1H); 4.761-4.735 (q, 1H);4.511-4.463 (q, 1H); 3.967-3.924 (t, 2H); 3.703 (s, 3H); 3.473 (s, 2H);3.019-2.977 (t, 2H); 2.443-2.394 (t, 2H); 2.233 (s, 6H); 1.944-1.897 (t,2H); 1.319-1.296 (d, 3H).

[1227]¹³C-nmr (CDCl₃): δ=172.292; 172.256; 169.808; 158.747; 130.731;127.887; 115.149; 112.900; 112.672; 66.690; 56.945; 54.039; 52.971;49.400; 46.105; 43.302; 37.421; 28.129; 19.029.

[1228] C₂₆H₃₃F₂N₃O₅ (MW=505); mass spectroscopy (MH⁺) 506.

EXAMPLE 14 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalanineMethyl Ester

[1229] Following General Procedure AE and using tert-butyl bromoacetate(Aldrich) and N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosinemethyl ester (from Example 15 below), the title compound was prepared asa solid (mp =116-119° C.). The reaction was monitored by tlc (Rf=0.54in50% EtOAc/hexanes) and the product was purified by silica gel columnchromatography.

[1230] NMR data was as follows:

[1231]¹H-nmr (CDCl₃): δ=7.648-7.615 (d, 1H); 7.513-7.407 (d, 1H);6.943-6.914 (d, 2H); 6.756-6.669 (d+t, 4H); 6.621-6.562 (t, 1H);4.662-4.590 (q+quintex, 2H); 4.382 (s, 2H); 3.571 (s, 3H); 3.406 (s,2H); 3.006-2.648 (m, 2H); 1.417 (s, 9H); 1.243-1.221 (d, 3H).

[1232]¹³C-nmr (CDCl₃): δ=173.14; 173.001; 172.294; 170.273; 168.614;168.546; 165.107; 161.816; 157.428; 139.493; 130.749; 129.385; 115.077;112.803; 103.250; 828.270; 66.039; 54.361; 52.730; 49.172; 42.832;37.288; 28.509; 19.018.

[1233] C₂₇H₃₂F₂N₂O₇ (MW=534); mass spectroscopy (MH⁺) 535.

EXAMPLE 15 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tyrosine Methyl Ester

[1234] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-tyrosine methyl ester (Bachem), the title compound was prepared as asolid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50%EtOAc/hexanes) and the product was purified by silica gel columnchromatography.

[1235] NMR data was as follows:

[1236] H-nmr (CDCl₃): δ=8.036 (b, 1H); 7.369-7.344 (d, 1H); 7.205-7.151(d, 1H); 6.869-6.841 (d, 2H); 6.763-6.738 (d, 2H); 6.657-6.615 (m, 3H);4.741-4.697 (q, 1H); 4.566-4.491 (q, 1H); 3.671 (s, 3H); 3.415 (s, 2H);3.061-2.771 (dm, 2H); 1.271-1.250 (d, 3H).

[1237]¹³C-nmr (CDCl₃): δ=173.049; 172.666; 172.444; 170.768; 165.211;161.917; 156.098, 130.862; 127.542; 116.093, 112.990; 112.659; 103.236;61.112; 54.306; 49.441; 42.947; 18.923.

[1238] C₂₁H₂₂F₂N₂O₅ (MW=420); mass spectroscopy (MH⁺) 421.

EXAMPLE 16 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4(carboxymethoxy)phenylalanineMethyl Ester

[1239] Following General Procedure N and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalaninemethyl ester (from Example 14 above), the title compound was prepared.The reaction was monitored by tlc (Rf=0.49 in 10% MeOH/DCM +1% AcOH) andthe product was purified by silica gel column chromatography.

[1240] NMR data was as follows:

[1241]¹H-nmr (CDCl₃): δ=7.817 (s, 1H); 7.648-7622 (d, 1H); 7.544-7.520(d, 1H); 6.956-6.914 (d, 2H); 6.762-6.703 (d+d, 4H); 6.650-6.590 (t,1H); 4.678-4.636 (q, 1H); 4.567-4.503 (quinex +s, 3H); 3.622 (s, 3H);3.431 (s, 2H); 2.987-2.811 (m, 2H); 1.241-1.219 (d, 3H).

[1242]¹³C-nmr (CDCl₃): δ=173.618; 173.534; 172.215; 171.209; 171.108;165.148; 164.973; 161.855; 161.683; 157.309; 139.052; 130.887; 129.376;115.104; 112.895; 112.667; 103.083; 65.324; 54.155; 52.933; 50.538;49.384; 42.683; 37.168; 18.678.

[1243] C₂₃H₂₄F₂N₂O₇ (MW=478); mass spectroscopy (MH⁺) 479.

EXAMPLE 17 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalanineMethyl Ester

[1244] Following General Procedure AD and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester(from Example 15 above) and 4-(2-hydroxyethyl)morpholine (Aldrich), thetitle compound was prepared as a solid (mp=138-141° C.). The reactionwas monitored by tlc (Rf =0.56 in 10% MeOH/DCM +1% TEA) and the productwas purified by silica gel column chromatography, followed by trituationusing diethyl ether.

[1245] NMR data was as follows:

[1246]¹H-nmr (CDCl₃): δ=6.974-6.945 (d, 2H); 6.795-6.726 (d+t, 2H);6.697-6.682 (t, 1H); 4.755-4.689 (q, 1H); 4.535-4.468 (quintex, 1H);4.050-4.012 (t, 2H); 3.723-3.606 (t+s, 7H); 3.463 (s, 2H); 3.039-2.892(m, 2H); 2.779-2.741 (t, 2H); 2.562-2.531 (t, 4H); 1.297-1.274 (d, 3H).

[1247]¹³C-nmr (CDCl₃): δ=1721.477; 172.428; 172.303; 169.925; 158;397;130.778; 128.504; 115.179; 112.988; 112.769; 112.659; 67.457; 66.249;58.187; 54.631; 54.119; 52.956; 49.358; 43.202; 37.496; 19.028.

[1248] C₂₇H₃₃F₂N₃O₆ (MW=533); mass spectroscopy (MH⁺) 534.

EXAMPLE 18 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylmino)hexanoate

[1249] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andNe,NEimethyl-L-lysine methyl ester hydrochloride (Bachem), the titlecompound was prepared as a solid (mp=123-126° C.). The reaction wasmonitored by tlc (Rf=0.22 in 10% MeOH/DCM+1% TEA) and the product waspurified by silica gel column chromatography.

[1250] NMR data was as follows:

[1251] H-nmr (CDCl₃): δ=7.019-6.993 (d, 1H); 6.828-6.801 (dd, 2H);6.753-6.723 (m, 1H); 6.617-6.592 (d, 1H); 4.557-4.447 (q+q, 2H); 3.730(s, 3H); 3.522 (s, 2H); 2.593-2.572 (m, 2H); 2.196 (s, 6H); 1.837-1.642(m, 2H); 1.486-1.344 (m+d, 7H).

[1252]¹³C-nmr (CDCl₃): δ=173.070; 172.544, 169.809; 112.986; 112.655;103.384: 59.393; 52.991; 49.368; 45.947; 43.427; 43.403; 43.375; 31.870;27.376; 23.378; 19.155.

[1253] C₂₀H₂₉F₂N₃O₄ (MW=413); mass spectroscopy (MH⁺) 414.

EXAMPLE 19 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate

[1254] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl(S)-2-amino-3-(2-pyridyl)propionate hydrochloride (Synthetech), thetitle compound was prepared as a solid (mp=121-124° C.). The reactionwas monitored by tlc (Rf=0.39 in 10% MeOH/DCM) and the product waspurified by silica gel column chromatography.

[1255] NMR data was as follows:

[1256]¹H-nmr (CDCl₃): δ=8.474-8.458 (d, 1H); 7.767-7.631 (m, 1H);7.625-7.574 (t, 1H); 7.178-7.102 (t+d, 2H); 6.818-6.811 (d, 2H);6.734-6.667 (t, 1H); 6.593-6.542 (m, 1H); 4.9334.873 (m, 1H);4.566-4.496 (m, 1H); 3.646 (s, 3H); 3.499 (s, 2H); 3.375-3.196 (m, 2H);1.393-1.370 (d, 3H).

[1257]¹³C-nmr (CDCl₃): δ=172.453; 172.020; 169.527; 157.454; 149.608;137.449; 124.366; 124.328; 122.694; 113.032; 112.992; 112.661; 103.333;53.032; 52.997; 52.349; 52.252; 49.427; 49.405; 43.464, 43.437, 38.486;19.548; 19.232.

[1258] C₂₀H₂₁F₂N₃O₄ (MW=405); mass spectroscopy (MH⁺) 406.

EXAMPLE 20 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(3-pyridyl)propionate

[1259] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and methyl(S)-2-amino-3-(3-pyridyl)propionate hydrochloride (Synthetech), thetitle compound was prepared as a solid (mp 101-103° C.). The reactionwas monitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product waspurified by silica gel column chromatography.

[1260] NMR data was as follows:

[1261]¹H-nmr (CDCl₃): δ=8.492-8.396 (m, 1H); 8.359-8.322 (m, 1H);7.505-7.452 (m, 1H); 7.248-7.170 (m, 1H); 6.976-6.908 (m, 1H);6.855-6.668 (m, 3H); 6.352-6.288 (m, 1H); 4.866-4.798 (m, 1H);4.784-4.429 (m, 1H); 3.750 (s, 3H); 3.513 (s, 2H); 3.220-2.964 (m, 2H);1.310-1.287 (d, 3H).

[1262]¹³C-nmr (CDCl₃): δ=172.867; 171.831; 170.307; 161.942; 150.892;150.753; 148.907; 148.750; 137.523; 137.388; 132.460; 124.106; 124.034;112.981; 112.754; 103.228; 53.623; 53.461; 53.146; 49.368; 49.259;43.137; 43.115; 43.086; 35.485; 18.664.

[1263] C₂₀H₂₁F₂N₃O₄ (MW=405); mass spectroscopy (MH⁺) 406.

EXAMPLE 21 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-proline Methyl Ester

[1264] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-proline methyl ester hydrochloride (Bachem), the title compound wasprepared as a viscous solid. The reaction was monitored by tlc(Rf=0.57in 10% MeOH/DCM) and the product was purified by acid/base washes.

[1265] NMR data was as follows:

[1266] H-nmr (CDCl₃): δ=7.524-7.498 (d, 1H); 6.813-6.793 (d, 2H);6.681-6.613 (m, 1H); 4.788-4.717 (m, 1H); 4.484-4.442 (m, 1H);3.705-3.590 (m+s, 4H); 3.465 (s, 2H); 2.217-1.902 (m, 5H); 1.332-1.309(d, 3H).

[1267]¹³C-nmr (CDCl₃): δ=172.753; 172.152; 169.843; 165.185; 161.894;112.953; 112.850; 112.727; 112.624; 103.331, 102.996, 102.662; 59.352;52.735; 47.495; 47.267; 43.069; 29.472; 25.403; 18.243.

[1268] C₁₇H₂₀F₂N₂O₄ (MW=354); mass spectroscopy (MH⁺) 355.

EXAMPLE 22 Synthesis of Methyl1-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate

[1269] Following General Procedure B and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and methylpipecolinate hydrochloride (Aldrich), the title compound was prepared asan oil. The reaction was monitored by tlc (Rf=0.30 in 50% EtOAc/hexanes)and the product was purified by silica gel chromatography.

[1270] NMR data was as follows:

[1271]¹H-nmr (CDCl₃): δ=7.2 (m, 5H), 6.95 (dd, J=7.2, 15.2, 7.2 Hz, 1H),5.21 (dd, J=5.0, 11.0, 5.0 Hz, 1H), 4.89 (q, J=7.1, 7.1 Hz, 1H), 3.7 (m,1H), 3.59 (s, 3H), 3.47 (s, 2H), 3.1 (m, 1H), 2.16 (d, J=11.5 Hz, 1H),1.4 (m, 4H), 1.22 (dd, J=1.3, 4.4, 1.2 Hz, 3H).

[1272]¹³C-nmr (CDCl₃): δ=172.6, 171.8, 170.7, 135.5, 129.8, 129.3,127.6, 52.9, 52.8, 46.0, 43.9, 27.1, 26.8, 25.6, 21.4, 19.9, 18.5.

[1273] C₁₈H₂₄N₂O₄ (MW=332); mass spectroscopy (MI+) 333.

EXAMPLE 23 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate

[1274] Step A—Preparation of 3-(3-pyridyl)alanine methyl esterdihydrochloride

[1275] Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) anddiethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolylchloridehydrochloride (5.00 g, 30.5 mmol) were added. The mixture was heated toreflux for 6 hours, and then cooled and filtered to remove NaCl (washedwith EtOH). The solvent was removed in vacuo and the mixture was takenup into saturated aqueous NaHCO₃ (100 mL) and extracted with EtOAc(3×100 mL). The solvent was removed and the residue purified by silicagel flash chromatography (95:5 CH₂Cl₂/MeOH) to give diethyl2-(3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%).

[1276] Diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate was dissolved in6N HCl (30 mL) and heated to reflux for 19 hours whereupon it was cooledto room temperature and the HCl solution was removed by evaporation invacuo. The intermediate amino acid dihydrochloride salt was taken upinto MEOH (30 mL) saturated with HCl gas and stirred for 3.5 hours. TheMeOH/HCl was removed by evaporation in vacua to give3-(3-pyridyl)alanine methyl ester dihydrochloride (2.235 g, 100%).

[1277] Step B—Preparation of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4pyridyl)propionate

[1278] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-3-(4-pyridyl)propionate hydrochloride (prepared bythe method set forth above using 4-picolylchloride hydrochloride), thetitle compound was prepared as a solid. The reaction was monitored bytlc (Rf=0.49 in 10% MeOH/DCM) and the product was purified by silica gelcolumn chromatography.

[1279] NMR data was as follows:

[1280]¹H-nmr (CDCl₃): δ=8.423-8.335 (dd, 2H); 7.832-7.754 (q, 1H);7.342-7.246 (dd, 1H); 7.032-6.972 (dd, 2H); 6.764-6.667 (t, 2H);6.659-6.599 (m, 1H); 4.837-4.768 (m, 1H); 4.590-4.515 (m, 1H); 3.675 (s,3H); 3.426 (s, 2H); 3.112-2.804 (m, 2H); 1.256-1.106 (dd, 3H).

[1281]¹³ C-nmr (CDCl₃): δ=173.037; 171.739; 170.258; 170.225; 165.201;165.012; 161.904; 161.721; 150.183; 150.063; 146.115; 146.012; 139.100;125.180; 125.122; 112.951; 112.915; 112.846; 103.492; 103.153; 53.088,49.318; 42.977, 37.593; 37.547; 19.297; 18.882.

[1282] C₂₀H₂₁F₂N₃O₄ (MW=405); mass spectroscopy (MH⁺) 406.

EXAMPLE 24 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino3-methoxypropionate

[1283] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-3-methoxypropionate hydrochloride (Bachem), the titlecompound was prepared as a solid (mp=165-168° C.). The reaction wasmonitored by tlc (Rf=0.48 in 10% MeOH/DCM) and the product was purifiedby acid/base washes.

[1284] NMR data was as follows:

[1285]¹H-nmr (CDCl₃): δ=6.971-6.944 (d, 1H); 6.813-6.801 (m, 2H);6.741-6.678 (m, 1H); 6.585-6.526 (m, 1H); 4.692-4.561 (quintex+q, 2H);3.836 3.802 (m, 1H); 3.738 (s, 3H); 3.592-3.516 (m+ds, 3H); 3.312 (s,3H); 1.408- 1.355 (dd, 3H).

[1286]¹³ C-nmr (CDCl₃): δ=172.705; 172.680; 170.908; 113.019; 112.978;112.687; 112.646; 103.347; 72.434; 72.405; 59.885; 59.837; 53.263;53.240; 49.413; 49.329; 19.389; 18.9196.

[1287] C₁₆H₂₀F₂N₂O₅ (MW=358); mass spectroscopy (MH⁺) 359.

EXAMPLE 25 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate

[1288] Step A methyl (2-N-CBZ-amino)-3-morpholino-propionate

[1289] To a solution of N-CBZ-dehydro-alanine methyl ester (Sigma) inacetonitrile was added 2.0 equivalent of morpholine and 0.25 equivalentsof anhydrous ferric chloride. The mixture was stirred for 16 hours andmonitored by TLC. The solvent was stripped off and the residue extractedwith ethyl acetate and washed with 1N HCl. The aqueous layer wasbasified with 1N potassium carbonate to pH=9 and extracted with ethylacetate again, dried over sodium sulfate and rotovapped to dryness togive methyl (2-N-CBZ-amino)-3-morpholino-propionate as a clear tan oil.See Perez et al., Tetrahedron 51(3) 8355-62 (1995)

[1290] Step B MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate

[1291] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-3-morpholinopropionate hydrochloride (prepared by GeneralProcedure O above from methyl (2-N-CBZ-amino)-3-morpholino-propionate),the title compound was prepared as a viscous solid. The reaction wasmonitored by tlc (Rf=0.44 in 10% MeOH/DCM) and the product was purifiedby acid/base washes.

[1292] NMR data was as follows:

[1293]¹H-nmr (CDCl₃): δ=7.408-7.384 (d, 1H); 7.247-7.173 (m, 1H);6.774-6.614 (m+t, 3H); 4.605-4.468 (m, 1H); 3.667 (s, 3H); 3.642 (s,2H); 3.576-3.561 (t, 4H); 3.479-3.461 (s+s, 2H); 2.639-2.618 (d, 2H);2.395-2.366 (m, 4H); 1.344-1.307 (t, 3H).

[1294]¹³C-nmr (CDCl₃): δ=173.120; 172.245; 172.192; 170.275; 170.159;165.189; 165.020; 161.897; 161.727; 139.167; 112.937; 112.863; 112.759;112.610; 112.533; 103.103; 102.774; 67.379; 67.301; 59.346; 59.110;54.030; 52.936; 51.116; 49.283; 43.053; 18.980; 18.921.

[1295] C₁₉H₂₆F₂N₃O₅ (MW=413); mass spectroscopy (MH⁺) 414.

EXAMPLE 26 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L(2-morpholinoethoxy)phenylalaninamide

[1296] Following General Procedure K and using 2-methoxyethylamine(Aldrich) andN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)-phenylalaninemethyl ester (from Example 17 above), the title compound was prepared asa solid (mp=165-168° C.). The reaction was monitored by tlc (Rf=0.67 in10% MeOH/DCM+1% TEA) and the product was purified by acid/base washes.

[1297] NMR data was as follows:

[1298]¹H-nmr (CDCl₃): δ=8.258-8.232 (d, 1H); 8.014-7.989 (d, 1H);7.532-7.370 (t, 1H); 7.035-7.008 (d, 2H); 6.842-6.630 (m, 5H);4.980-4.905 (m, 1H); 4.794-4.772 (m, 1H); 4.026-3.992 (t, 2H);3.713-3.642 (t, 4H); 3.594-3.453 (dd, 2H); 3.404-3.267 (t, 2H); 3.179(s, 3H); 2.930-2.914 (t, 2H); 2.763-2.731 (t, 2H); 2.538-2.502 (m, 4H);1.335-1.314 (d, 3H).

[1299]¹³C-nmr (CDCl₃): δ=172.956; 172.918; 171.756; 170.142; 161.677;158.131; 130.973; 129.270; 114.968; 114.875; 112.908; 112.696; 112.571;71.423; 71.367; 67.440; 66.164; 59.072; 58.232; 58.188; 54.636; 42.827;42.800; 39.757; 39.642; 20.449; 20.135.

[1300] C₂₉H₃₈F₂N₄O₆ (MW=576); mass spectroscopy (MH⁺) 577.

EXAMPLE 27 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionamide

[1301] Following General Procedure K and using 2-methoxyethylamine(Aldrich) and methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate(from Example 24 above), the title compound was prepared as a solid(mp=181-184° C.). The reaction was monitored by tlc (Rf=0.43 in 10%MeOH/DCM) and the product was purified by acid/base washes.

[1302] NMR data was as follows:

[1303]¹H-nmr (CDCl₃): δ=6.728-6.706 (d, 2H); 6.648-6.586 (t, 1H);4.244-4213 (m, 1H); 4.092-4.068 (m, 1H); 3.553-3.503 (m, 2H);3.393-3.347 (m, 2H); 3.210-3.073 (m+s, 7H); 3.053 (s, 3H); 1.183-1.138(d, 3H).

[1304]¹³C-nmr (CDCl₃): δ=176.31; 173.28; 172.59; 141.65; 114.02; 113.79;113.69; 109.467; 103.528; 80.369; 73.210; 72.265; 72.011; 59.839;59.801; 59.374; 55.584; 51.773; 51.731; 51.445; 42.915; 40.846; 17.751.

[1305] C₁₈H₂₅F₂N₃O₅ (MW=401); mass spectroscopy (MH⁺) 402.

EXAMPLE 28 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine Methyl Ester

[1306] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andglycine methyl ester hydrochloride (Bachem), the title compound wasprepared as a solid (mp=158-160° C.). The reaction was monitored by tlc(Rf=0.61 in 10% MeOH/DCM) and the product was purified by silica gelchromatography.

[1307] NMR data was as follows:

[1308]¹H-nmr (CDCl₃): δ=6.882-6.866 (m, 1H); 6.827-6.794 (m, 2H);6.748-6.689 (t, 1H); 6.520-6.494 (d, 1H); 4.611-4.563 (quintex, 1H);4.00-3.99 (d, 2H); 3.746 (s, 3H); 3.528 (s, 2H); 1.389-1.366 (d, 3H).

[1309]¹³C-nmr (CDCl₃): δ=172.926; 172.524; 170.524; 113.056; 112.951;112.723; 103.769; 103.437; 103.214; 103.105; 85.309; 53.009; 49.333;43.292; 41.692; 18.810.

[1310] C₁₄H₁₆F₂N₂O₄ (MW=314); mass spectroscopy (MH⁺) 315.

EXAMPLE 29 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4pyridyl)propionamide

[1311] Following General Procedure K and using 2-methoxyethylamine andmethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(4-pyridyl)propionate(from Example 23 above), the title compound was prepared as a solid(mp=202-206° C). The reaction was monitored by tlc (Rf=0.72 in 10%MeOH/DCM) and the product was purified by acid/base washes.

[1312] NMR data was as follows:

[1313]¹H-nmr (CDCl₃): δ=8.214-8.198 (d, 2H); 7.117-7.100 (d, 2H);6.707-6.687 (m, 2H); 6.638-6.576 (t, 1H); 4.498-4.448 (m, 1H);3.985-3.939 (q, 1H); 3.386 (s, 2H); 3.190-3.084 (m, 4H); 3.060 (s, 3H);2.918-2.629 (m, 2H); 1.077-0.905 (d, 3H).

[1314]¹³C-nmr (CDCl₃): δ=175.831; 173.229; 150.440; 150.249; 126.887;113.995; 113.662; 103.662; 103.529; 72.081; 59.370; 55.201; 51.674;42.949; 40.889; 38.350; 17.933.

[1315] C₂₂H₂₆F₂N₄O₄ (MW=448); mass spectroscopy (MH⁺) 449.

EXAMPLE 30 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino3-(2-pyridyl)propionamide

[1316] Following General Procedure K and using 2-methoxyethylamine andmethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate(from Example 19 above), the title compound was prepared as a solid(mp=183-187° C.). The reaction was monitored by tlc(Rf=0.39 in 10%MeOH/DCM) and the product was purified by recrystallization fromMeOH/DCM.

[1317] NMR data was as follows:

[1318]¹H-nmr (CDCl₃): δ=8.457-8.442 (d, 1H); 8.029-8.005 (d, 1H);7.642-7.585 (t, 1H); 7.395-7.379 (m, 1H); 7.267-7.141 (d+t, 2H);6.828-6.802 (m, 2H); 6.754-6.679 (t, 1H); 6.604-6.581 (m, 1H);4.871-4.809 (q, 1H); 4.532- 4.485 (quintex, 1H); 3.537 (s, 2H);3.342-3.118 (m, 6H); 3.248 (s, 3H); 1.394-1.371 (d, 3H).

[1319]¹³C-nmr (CDCl₃): δ=172.360; 171.140; 158.43; 149.113; 137.59;124.98; 122.54; 113.02; 112.69; 103.40; 71.376; 59.203; 53.143; 49.984;43.355; 43.328; 39.685; 39.626; 19.295.

[1320] C₂₂H₂₆F₂N₄O₄ (MW=448); mass spectroscopy (MH⁺) 449.

EXAMPLE 31 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4yl)propionate

[1321] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-3-(thiazol-4-yl)propionate hydrochloride (GeneralProcedure H with methanol and HCl on methyl(S)-2-amino-3-(thiazol-4-yl)propyl acid (Synthetech)), the titlecompound was prepared as a solid (mp=136-139° C.). The reaction wasmonitored by tlc (Rf=0.4 in 10% MeOH/DCM) and the product was purifiedby recrystallization from DCM.

[1322] NMR data was as follows:

[1323]¹H-nmr (CDCl₃): δ=8.737-8.731 (d, 1H); 7.410-7.385 (d, 1H);7.065-7.059 (d, 1H); 6.828-6.802 (m, 2H); 6.747-6.687 (m, 1H);6.542-6.518 (d, 1H); 4.904-4.844 (q, 1H); 4.553-4.505 (quintex, 1H);3.678 (s, 3H); 3.515 (s, 2H); 3.402-3.232 (dq, 2H); 1.384-1.361 (d, 3H).

[1324]¹³C-nmr (CDCl₃): δ=172.497; 171.726; 169.619; 153.831; 152.613;116.431; 113.019; 112.688; 112.014; 103.396; 53.113; 52.625; 49.476;43.460; 43.435; 32.850; 19.422.

[1325] C₁₈H₁₉F₂N₃O₄S (MW=411); mass spectroscopy (MH⁺) 412.

EXAMPLE 32 Synthesis of Methyl2-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1,2,3,4tetrahydroisoquinoline-3-carboxylate

[1326] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the titlecompound was prepared as a solid (mp=37-40° C). The reaction wasmonitored by tlc (Rf=0.64 in 10% MeOH/DCM).

[1327] NMR data was as follows:

[1328]¹H-nmr (CDCl₃): δ=7.500-7.475 (d, 1H); 7.161-7.057 (m, 4H);6.815-6.795 (dm, 2H); 6.656-6.596 (t, 1H); 5.336-5.088 (m, 2H);4.924-4.841 (m, 1H); 4.718-4.453 (m, 1H); 3.530 (s, 3H); 3.500 (s, 2H);3.329-3.058 (m, 2H); 1.423-1.400, 1.327-1.304 (d, 3H).

[1329]¹³C-nmr (CDCl₃): δ=173.428; 173.329; 171.690; 171.559; 169.558;165.020; 161.899; 161.728; 139.368; 132.549; 128.912; 127.723; 126.648;112.929; 103.360; 60.915; 53.318; 53.001; 46.377; 43.121; 31.027;21.537; 19.545; 18.771; 14.716.

[1330] C₂₂H₂₂F₂N₂O₄ (MW=416); mass spectroscopy (MH⁺) 417.

EXAMPLE 33 Synthesis ofN-(3-Methoxybenzyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1331] Following General Procedure B and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared bycoupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above)with L-phenylalanine methyl ester hydrochloride (Sigma) using GeneralProcedure E, followed by hydrolysis using General Procedure C) and3-methoxybenzylamine TCI), the title compound was prepared as a solid(mp=117-130° C.). The reaction was monitored by tlc (Rf=0.8 in 3%MeOH/methylene chloride) and the product was purified byrecrystallization from MeOH.

[1332] NMR data was as follows:

[1333]¹H-nmr (DMSO-d₆): δ=8.4 (t, 1H), 8.32 (d, 1H), 8.1 (d, 1H),6.95-7.2 (m, 9H), 6.7 (m, 3H), 4.5 (m, 1H), 4.2 (m, 3H), 3.7 (s, 3H),3.5 (s, 2H), 3.3 (d, 2H), 3.0 (m, 2H), 2.5 (s, 3H), 1.2 (m, 4H).

[1334]¹³C-nmr (DMSO-d₆): δ=172.40, 171.08, 169.28, 159.62, 141.09,138.06, 129.62, 129.51, 128.41, 126.63, 119.56, 112.97, 112.79, 112.59,112.46, 55.31, 48.77, 40.69, 40.42, 40.28, 40.14, 40.03, 39.86, 39.70,39.58, 39.46, 39.44, 39.31, 39.20, 39.03, 18.45.

[1335] C₂₈H₂₉N₃O₄F₂ (MW=509); mass spectroscopy (MH⁺) 509.

EXAMPLE 34 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(1-naphthyl)propionate

[1336] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-3-(1-naphthyl)propionate hydrochloride (Bachem), thetitle compound was prepared as a solid (mp=103-130° C.). The reactionwas monitored by tlc (Rf=0.8 in 5 % MeOH/methylene chloride) and theproduct was purified by flash column chromatography using 6%MeOH/methylene chloride as the eluent.

[1337] NMR data was as follows:

[1338]¹H-nmr (CDCl₃): δ=8.10 (d, 1H), 7.85 (d, 1H), 7.71 (d, 1H), 7.50(m, 3H), 7.35 (t, 1H), 7.20 (d, 1H), 6.70 (m, 4H), 6.30 (d, 1H), 4.90(m, 1H), 4.45 (m, 1H), 3.3-3.7 (m, 8H), 1.7 (bs, 1H), 1.3 (d 3H).

[1339]¹³C-nmr (CDCl₃): δ=172.43, 172.29, 169.77, 134.41, 132.61, 132.58,129.51, 128.63, 128.33, 128.28, 128.06, 126.97, 126.80, 126.42, 126.29,125.94, 125.86, 124.06, 123.90, 112.96, 112.63, 103.44, 78.03, 77.61,77.19, 61.01,.54.02, 53.83, 52.99, 51.40, 49.33, 43.29, 35.64, 18.82,14.77.

[1340] C₂₄H₂₄N₂O₄F₂ (MW=442); mass spectroscopy (MH⁺) 442.

EXAMPLE 35 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(2-naphthyl)propionate

[1341] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-3-(2-naphthyl)propionate hydrochloride (Bachem), thetitle compound was prepared as a solid (mp=166° C.). The reaction wasmonitored by tlc (Rf=0.55 in 5% MeOH/methylene chloride) and the productwas purified by preparative tlc using 5 % MeOH/methylene chloride as theeluent.

[1342] NMR data was as follows:

[1343]¹H-nmr (CDCl₃): δ=1.3 (d, 3H), 3.2 (m, 2H), 3.3 (s, 2H), 3.7 (s,3H), 4.55 (m, 1H), 4.9 (quart, 1H), 6.7 (m, 4H), 7.05 (d, 1H), 7.20 (d,1H), 7.45 (m, 2H), 7.55 (s, 1H), 7.80 (m, 3H).

[1344]¹³C-nmr (CDCl₃): δ=172.43, 172.26, 169.86, 133.93, 133.76, 133.02,128.86, 128.64, 128.23, 128.20, 127.69, 126.85, 126.45, 112.95, 112.62,103.37, 78.05, 77.62, 77.20, 53.93, 53.05, 49.37, 43.12, 38.46, 18.81.

[1345] C₂₄H₂₄N₂O₄F₂ (MW=442); mass spectroscopy (MH⁺) 442.

EXAMPLE 36 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propionate

[1346] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-3-(2-thienyl)-propionate (Bachem), the title compoundwas prepared as a solid (mp=145-147° C.). The reaction was monitored bytlc (Rf=0.9 in 100% EtOAc) and the product was purified by preparativetlc using EtOAc as the eluent.

[1347] NMR data was as follows:

[1348]¹H-nmr (CDCl₃): δ=7.15 (d, 1H), 6.9 (t, 1H), 6.7-6.8 (m, 5H); 6.3(d, H), 4.8 (m, 1H), 4.5 (m, 1H), 3.8 (s, 3H), 3.5 (s, 2H), 3.35 (d,2H), 1.35 (d, 3H).

[1349]¹³C-nmr (CDCl₃): δ=172.22, 171.56, 169.79, 137.47, 127.71, 125.55,113.04, 112.71, 103.48, 78.03, 77.60, 77.18, 53.78, 53.25, 49.51, 43.41,32.37, 18.97.

[1350] C₁₉H₂₀N₂O₄F₂S (MW=410); mass spectroscopy (MH⁺) 410.

EXAMPLE 37 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylaianine Benzyl Ester

[1351] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-phenylalanine benzyl ester hydrochloride (Bachem), the title compoundwas prepared as a solid (mp=170-171° C.). The reaction was monitored bytlc (Rf=0.7 in 5% MeOH/methylene chloride) and the product was purifiedby recrystallization from MeOH.

[1352] NMR data was as follows:

[1353]¹H-nmr (MeOH): δ=7.3 (m, 10H), 6.9 (m, 3H), 5.2 (s, 2H), 4.75 (t,J=7 Hz, 1H), 4.4 (quart, J=6 Hz, 1H), 3.6 (s, 2H), 3.1 (m, J=6 Hz, 2H),1.35 (d, J=7 Hz, 3H).

[1354]¹³C-nmr (MeOH): δ=175.29, 173.09, 172.78, 141.54, 138.35, 137.53,130.88, 130.08, 130.05, 129.92, 128.42, 113.93, 113.83, 113.60, 103.90,103.55, 103.21, 68.59, 55.87.

[1355] C₂₇H₂₆N₂O₄F₂ (MW=480); mass spectroscopy (MH⁺) 480.

EXAMPLE 38 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine3-Bromopropyl Ester

[1356] Following General Procedure B and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared bycoupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above)and L-phenylalanine (Aldrich) using General Procedure B) and3-bromo-1-propanol (Aldrich), the title compound was prepared as a solid(mp=138-142° C.). The reaction was monitored by tlc (Rf=0.75 in 60%EtOAc/hexanes) and the product was purified by flash columnchromatography using 60% EtOAc/hexanes as the eluent.

[1357] NMR data was as follows:

[1358]¹H-nmr (CDCl₃): δ=7.3-6.6 (m, 10H), 4.8 (m, 1H), 4.55 (m, 1H), 4.2(t, J=6 Hz, 2H), 3.51 (s, 2H), 3.3 (m, 2H), 3.05 (m, J=6 and 8 Hz, 2H),2.1 (m, 2H), 1.3-1.2 (m, J=7 Hz, 3H).

[1359]¹³C-nmr (CDCl₃): δ=172.49, 171.78, 171.71, 170.01, 169.96, 165.31,162.02, 161.84, 138.91, 138.78, 138.66, 136.26, 136.19, 129.76, 129.72,129.22, 129.18, 127.80, 113.04, 113.02, 112.93, 112.91, 112.82, 112.79,112.71, 112.69, 103.72, 103.69, 103.36, 103.05, 103.03, 63.75, 63.70,54.11, 53.91, 49.38, 49.32, 43.26, 38.56, 38.51, 31.92, 29.76, 29.71,19.14, 19.06.

[1360] C₂₃H₂₅N₂O₄F₂Br (MW=511.1); mass spectroscopy (MH⁺) 512.

EXAMPLE 39 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-IodopropylEster

[1361] Following General Procedure B and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (prepared bycoupling N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above)and L-phenylalanine (Aldrich) using General Procedure B) and3-iodo-1-propanol (Aldrich) , the title compound was prepared as asolid. The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/methylenechloride) and the product was purified by preparative tlc using 5 %MeOH/methylene chloride.

[1362] NMR data was as follows:

[1363]¹H-nmr (CDCl₃): δ=7.4-7.0 (m, 5H), 6.9-6.6 (m, 4H), 6.3 (m, 1H),4.8 (m, 1H), 4.5 (m, 1H), 4.2 (t, 2H), 3.5 (s, 2H), 3.1 (m, 4H), 2.1 (m,2H), 1.7 (s, 1H), 1.35-1.25 (m, 3H).

[1364]¹³C-nmr (CDCl₃): δ=172.24, 171.72, 169.95, 136.12, 136.09, 129.77,129.75, 129.28, 129.24, 127.87, 113.06, 113.02, 112.73, 112.70, 103.80,103.49, 103.47, 65.73, 65.70, 54.00, 53.84, 49.42, 49.33, 43.38, 38.54,38.50, 32.57, 18.97, 18.91.

EXAMPLE 40 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-leucine tert-Butyl Ester

[1365] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-leucine tert-butyl ester hydrochloride (Bachem), the title compoundwas prepared as a solid (mp=128° C.). The reaction was monitored by tlc(Rf=0.85 in 5% MeOH/methylene chloride) and the product was purified byflash column chromatography using 5% MeOH/methylene chloride as theeluent.

[1366] NMR data was as follows:

[1367]¹H-nmr (CDCl₃): δ=6.9-6.5 (m, 5H), 4.6 (m, 1H), 4.4 (m, 1H), 3.5(s, 2H), 1.7-1.4 (m, 15H), 0.9 (t, 6H).

[1368]¹³C-nmr (CDCl₃): δ=172.41, 172.20, 169.87, 165.30, 162.00, 161.83,139.01, 138.89, 112.92, 112.82, 112.69, 112.59, 103.62, 103.29, 102.95,82.50, 78.03, 77.61, 77.18, 52.12, 49.39, 43.34, 41.86, 28.52, 25.42,23.26, 22.46, 19.18.

[1369] C₂₇H₃₀N₂O₄F₂ (MW=412.48); mass spectroscopy (MH⁺) 413.

EXAMPLE 41 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamide

[1370] Following General Procedure L and using ethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate(from Example 65 below), the title compound was prepared as a solid. Thereaction was monitored by tlc (Rf 0.1 in 9: 1 CHCl₃/MeOH) and theproduct was purified by recrystallizaion from EtOH.

[1371] NMR data was as follows:

[1372]¹H-nmr (DMSO-d₆): δ=8.54 (m, 1H), 8.43 (d, 1H), 7.77 (m, 1H), 7.59(bs, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 7.22 (m, 1H), 7.09 (m, 1H), 6.98(m, 2H), 5.41 (m, 1H), 4.46 (m, 1H), 4.46 (m, 1H), 3.52 (s, 2H), 1.26(m, 3H).

[1373] C₁₈H₁₇N₃O₃F₂ (MW=376.3); mass spectroscopy (MH⁺) 377.

EXAMPLE 42 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamide

[1374] Following General Procedure L and using ethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate(from Example 53 below), the title compound was prepared as a solid. Thereaction was monitored by tlc (Rf=0.1 in 9:1 CHCl₃/MeOH) and the productwas purified by recrystallization from EtOH.

[1375] NMR data was as follows:

[1376]¹H-nmr (DMSO-d₆): δ=8.64 (m, 1H), 8.55 (d, 1H), 8.52 (d, 1H), 8.41(d, 1H), 7.79 (m, 1H), 7.37 (m, 1H), 7.32 (m, 1H), 7.09 (m, 1H), 6.98(m, 2H), 5.42 (m, 1H), 4.42 (m, 1H), 3.53 (s, 2H), 1.26 (m, 3H).

[1377] C₁₈H₁₇N₄O₃F₂ (MW=376.3); mass spectroscopy (MH⁺) 377.

EXAMPLE 43 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-N-(tert-butoxycarbonyl)-L-lysineMethyl Ester

[1378] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andNE-(tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the titlecompound was prepared as an oil. The reaction was monitored by tlc(Rf=0.40 in 50% EtOAc/hexanes) and the product was purified by flashchromotography using 50% EtOAc/hexanes as the eluent.

[1379] NMR data was as follows:

[1380]¹H-nmr (CDCl₃): δ=6.80 (d, 2H), 6.66 (t, 1H), 4.82 (bs, 1H), 3.73(s, 3H), 3.52 (s, 2H), 3.04 (bs, 2H), 1.60-1.15 (m, 2H), 1.38 (s, 9H),1.32 (d, 2H), 1.20-1.30 (m, 2H).

[1381]¹³C-nmr (CDCl₃): δ=173.00, 172.80, 165.28, 165.11, 161.98, 161.78,156.79, 138.95, 129.06, 128.72, 103.59, 103.26, 102.92, 79.81, 52.99,52.76, 49.44, 43.25, 31.92, 29.98, 28.99, 22.95, 18.94.

[1382] C₂₃H₃₃F₂N₃O₆ (MW=485.53); mass spectroscopy (MH⁺) N/A.

EXAMPLE 44 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino4-phenylbutanoate

[1383] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-4-phenylbutanoate (prepared from(+)-α-amino-4-phenylbutyric acid (Bachem) using General Procedure AG),the title compound was prepared as a solid (mp=147-149.5° C). Thereaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes) and theproduct was purified by flash chromotography using EtOAc/hexanes as theeluent.

[1384] NMR data was as follows:

[1385]¹H-nmr (CDCl₃): δ=7.63 (bd, 2H), 7.04 (m, 5H), 6.56-6.82 (m, 3H),4.80 (p, 1H), 4.48 (q, 1H), 3.65 (s, 3H), 3.49 (s, 2H), 2.50-2.65 (m,2H), 1.80-2.16 (m, 2H), 1.29 (d, 3H).

[1386]¹³C-nmr (CDCl₃): δ=173.48, 172.89, 170.43, 165.17, 161.71, 140.91,139.34, 129.07, 129.01, 128.89, 126.81, 126.76, 112.90, 112.67, 103.37,103.03, 102.69, 52.86, 52.71, 49.36, 42.99, 33.79, 32.21, 19.34.

[1387] C₂₂H₂₄F₂N₂O₄ (MW=418.44); mass spectroscopy (MH⁺) 419.

EXAMPLE 45 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine 2-Phenylethyl Ester

[1388] Following General Procedure X and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared fromN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (fromExample 73 below) using General Procedure O) and 2-phenylethanol(Aldrich), the title compound was prepared as a solid (mp=154.0-155.2°C.). The reaction was monitored by tlc (Rf=0.15 in 15% EtOAclhexanes)and the product was purified by flash chromotography using 15%EtOAc/hexanes as the eluent.

[1389] NMR data was as follows:

[1390]¹H-nmr (CDCl₃): δ=7.35-7.20 (m, 5H), 6.76 (bs, 1H), 6.72-6.67 (m,3H), 6.54 (bd, 1H), 4.58 (p, 1H), 4.34 (t, 2H), 3.96 (d, 2H), 3.52 (s,2H), 2.93 (t, 2H), 1.26 (d, 3H).

[1391]¹³C-nmr (CDCl₃): δ=172.9, 170.1, 169.9, 137.8, 129.4, 129.1,127.3, 112.94, 103.4, 103.0, 65.5, 49.3, 43.2, 41.8, 35.4, 18.8.

[1392] C₂₁H₂₂N₂O₄F₂ (MW=404.42); mass spectroscopy (MH⁺) 405.

EXAMPLE 46 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine 3-Phenylpropyl Ester

[1393] Following General Procedure X and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared fromN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (fromExample 73 below) using General Procedure O) and and 3-phenyl-1-propanol(Aldrich), the tide compound was prepared as a solid (mp=137° C.). Thereaction was monitored by tdc (Rf=0.15 in 50% EtOAc/hexanes) and theproduct was purified by flash chromatography using 50% EtOAc/hexanes asthe eluent.

[1394] NMR data was as follows:

[1395]¹H-nmr (CDCl₃): δ=7.55-7.32 (m, 5H), 6.73 (d, 2H), 6.65 (m, 1H),4.74 (p, 1H), 4.14 (t, 2H), 3.93 (m, 2H), 3.49 (s, 2H), 2.66 (t, 2H),1.94 (p, 2H), 1.41 (d, 3H).

[1396]¹³C-nmr (CDCl₃): δ=173.8, 170.5, 170.1, 165.2, 165.0, 161.9,161.7, 141.5, 139.2, 129.1, 128.9, 126.7, 112.9, 112.8, 103.4, 103.1,102.8, 65.4, 49.3, 42.9, 41.8, 32.6, 30.6, 19.3.

[1397] C₂₂H₂₄N₂O₄F₂ (MW=418.44); mass spectroscopy (MH⁺) 419.

EXAMPLE 47 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4pyridyl)acetamide

[1398] Following General Procedure L and using ethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate(from Example 66), the title compound was prepared as a solid. Thereaction was monitored by tlc (Rf=0.1 in CHCl₃/MeOH 9:1) and the productwas purified by silica gel chromatography using 9:1 CHCl₃/MeOH as theeluent.

[1399] NMR data was as follows:

[1400]¹H-nmr (DMSO-d₆): δ=8.53 (m, 2H), 8.88 (bs, 1H), 7.41 (m, 2H),7.12 (m, 1H), 7.02 (m, 2H), 5.46 (m, 1H), 4.46 (m, 1H), 3.55 and 3.52(s, 2H), 1.21 (m, 3H).

[1401] C₁₈H₁₈N₄O₃F₂ (MW=376.3); mass spectroscopy (MH⁺) 377.

EXAMPLE 48 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-threonineMethyl Ester

[1402] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-threoninemethyl ester hydrochloride (Bachem), the title compound was prepared asa solid.

[1403] NMR data was as follows:

[1404]¹H-nmr (CDCl₃): δ=7.45 (d, J=8.9 Hz, 1H), 7.11-7.27 (m, 6H), 4.55(quintet, J=7.2 Hz, 1H), 4.43 (dd, J=2.6,8.8 Hz, 1H), 4.20 (m, 1H), 3.62(s, 3H), 3.46 (s, 2H), 1.29 (d, J=7.0 Hz, 3H), 1.04 (d, J=6.4 Hz, 3H).

[1405]¹³C-nmr (CDCl₃): δ=172.8, 171.1, 170.9, 134.5, 128.9, 128.4,126.8, 67.5, 57.7, 52.1, 48.7, 42.8, 19.6, 18.3.

[1406] C₁₆H₂₂N₂O₅ (MW=322.36); mass spectroscopy (MH⁺) 323.

EXAMPLE 49 Synthesis of N′-[N-(Phenylacetyl)-L-alaninyl]-L-leucinamide

[1407] Following General Procedure T and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-leucinamidehydrochloride (Aldrich), the title compound was prepared as a solid(mp=207-209° C.). The product was purified by extraction with EtOAc andwashing with aqueous potassium carbonate and aqueous hydrochloric acid.

[1408] NMR data was as follows:

[1409]¹H-nmr (CD₃OD): δ=7.00-7.12 (m, 5H), 4.10-4.20 (m, 2H), 3.34 (s,2H), 1.30-1.50 (m, 2H), 1.12-1.23 (m, 4H), 0.65-0.76 (m, 6H).

[1410]¹³C-nmr (CD₃OD): δ=177.5, 174.9, 174.1, 136.8, 130.1, 129.6,127.9, 52.8, 50.7, 43.4, 41.9, 25.8, 23.5, 21.8, 17.7.

EXAMPLE 50 Synthesis of N′-[N-(Phenylacetyl)-L-alaninyl]-L-alaninamide

[1411] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-alaninamidehydrochloride (Bachem), the title compound was prepared as a solid(mp=>260° C.). The product was purified by washing with aqueous sodiumhydroxide and aqueous hydrochloric acid.

[1412] NMR data was as follows:

[1413]¹H-nmr (DMSO-d₆): δ=8.27 (d, J=7.1 Hz, 1H), 7.88 (d, J=7.6 Hz,1H), 7.26 (m, 6H), 6.99 (s, 1H), 4.25 (quintet, J=7.1 Hz, 1H), 4.16(quintet, J=7.1-Hz, 1H), 3.46 (s, 2H), 1.19 (t, J=6.3 Hz, 6H).

[1414]¹³C-nmr (DMSO-d₆): δ=174.1, 171.8, 170.0, 136.3, 129.0, 128.1,126.3, 48.3, 47.9, 42.0, 18.3, 18.1.

EXAMPLE 51 Synthesis ofN′-[N-(Phenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1415] Following General Procedure T and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andL-phenylalaninamide (Bachem), the title compound was prepared as a solid(mp=224-225° C.).

[1416] NMR data was as follows:

[1417]¹H-nmr (DMSO-d₆): δ=8.24 (d, J=7.2 Hz, 1H), 7.89 (d, J=8.2 Hz,1H), 7.36 (s, 1H), 7.13-7.34 (m, 10H), 7.11 (s, 1H), 4.40 (m, 11H), 4.21(quintet, J=7.1 Hz, 1H), 3.44 (d, 2H), 3.01 (dd, J=4.9, 13.7 Hz, 1H),2.82 (dd, J=9.0, 13.7 Hz, 1H), 1.13 (d, J=6.9 Hz, 31H).

[1418]¹³C-nmr (DMSO-d₆): δ=172.7, 172.0, 170.0, 137.8, 136.3, 129.2,129.0, 128.2, 128.0, 126.3, 126.2, 53.6, 48.5, 41.9, 37.3, 18.0.

EXAMPLE 52 Synthesis of N′-[N-(Phenylacetyl)-alanlinyl)-L-valinamide

[1419] Following General Procedure T and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-valinamidehydrochloride (Bachem), the title compound was prepared as a solid(mp=>261° C.).

[1420] NMR data was as follows:

[1421]¹H-nmr (DMSO-d₆): δ=8.31 (d, J=7.5 Hz, 1H), 7.62 (d, J=9.0 Hz,1H), 7.38 (s, 1H), 7.15-7.30 (m,- 5H), 7.05 (s, 1H), 4.34 (quintet,J=7.2 Hz, 1H), 4.08 (dd, J=6.4, 15.3 Hz, 1H), 3.45 (s, 2H), 1.91 (m,1H), 1.19 (d, J=7.0 Hz, 3H), 0.79 (d, J=6.7 Hz, 3H), 0.76 (d, J=6.8 Hz,3H).

[1422]¹³C-nmr (DMSO-d₆): δ=172.8, 172.1, 170.0, 136.3, 129.0, 128.2,126.3, 57.2, 48.2, 42.0, 30.5, 19.2, 17.9, 17.8.

EXAMPLE 53 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate

[1423] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(3-pyridyl)acetate (prepared as described in P. Kolar et al.,J. Heterocyclic Chem., 28, 1715 (1991) and references cited therein),the title compound was prepared as a solid (mp=146-157° C.). Thereaction was monitored by tlc (Rf=0.1 in CHCl₃/MeOH 98:2) and theproduct was purified by silica gel chromatography using 959:5 CHCl₃/MeOHas the eluent, followed by recrystallization from chlorobutane.

[1424] NMR data was as follows:

[1425]¹H-nmr (CDCl₃): δ=8.60 (m, 1H), 8.56 and 8.52 (m, 1H), 7.91 (m,1H), 7.63 (m, 1H), 7.22 (m, 1H), 6.90 (m, 1H), 6.74 (m, 2H), 5.55 (m,1H), 4.69 (m, 1H), 4.17 (m, 2H), 3.50 and 3.41 (s, 2H), 1.33 and 1.29(d, 3H), 1.21 (m, 3H), 1.18 (m, 3H).

[1426] C₂₀H₂₁N₃O₄F₂ (MW=405.4); mass spectroscopy (MH⁺) 405.

EXAMPLE 54 Synthesis ofN-Methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamnide

[1427] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN-methyl-L-leucinamide (prepared from N-methyl-N′-BOC-L-leucinamide(from Example D5 above) using General Procedure Y), the title compoundwas prepared as a solid (mp=233-235° C.). The product was purified byrecrystallization from MeOH.

[1428] NMR data was as follows:

[1429]¹H-nmr (CDCl₃/CD₃OD): δ=7.25-7.40 (m, 5H), 4.36 (quartet, J=7.2Hz, 1H), 4.27 (dd, J=5.1, 14.6 Hz, 1H), 3.56 (s, 2H), 2.72 (s, 3H),1.40-1.61 (m, 2H), 1.32 (d, J=7.1 Hz, 3H), 0.89 (d, J=6.2 Hz, 3H), 0.86(d, J=6.2.Hz, 3H).

EXAMPLE 55 Synthesis ofN,N-Dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1430] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN,N-dimethyl-L-phenylalaninamide (prepared by couplingN-BOC-L-phenylalanine (Bachem) with dimethylamine hydrochloride(Aldrich) using General Procedure B, followed by removal of theBOC-group using General Procedure Y), the title compound was prepared asa solid (mp=152-155° C.). The product was purified by extraction withEtOAc, washing with aqueous sodium carbonate and aqueous hydrochloricacid, and trituration with Et₂O.

[1431] NMR data was as follows:

[1432]¹H-nmr (CDCl₃): δ=7.49 (d, J=8.2 Hz, 1H), 7.20-7.26 (m, 8H), 7.14(m, 2H), 6.45 (d, J=7.5 Hz, 1H), 5.08 (quartet, J=8.0 Hz, 1H), 4.60(quintet, J=7.3 Hz, 1H), 3.56 (s, 2H), 2.95 (m, 2H), 2.86 (s, 3H), 2.61(s, 3H), 1.26 (d, J=6.9 Hz, 3H).

[1433]¹³C-nmr (CDCl₃): δ=171.6, 170.8, 170.4, 136.0, 134.7, 129.3,129.2, 128.9, 128.8, 128.3, 127.1, 50.2, 48.7, 43.4, 39.5, 36.8, 35.6,18.8.

EXAMPLE 56 Synthesis ofN,N-Dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamide

[1434] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN,N-dimethyl-L-leucinamide (prepared by coupling N-BOC-L-leucine(Bachem) with dimethylamine hydrochloride (Aldrich) using GeneralProcedure B, followed by removal of the BOC-group using GeneralProcedure Y), the title compound was prepared as a solid (mp=130-132°C.). The product was purified by extraction by EtOAc, washing withaqueous sodium carbonate and aqueous hydrochloric acid, and triturationwith EtO.

[1435] NMR data was as follows:

[1436]¹H-nmr (CDCl₃): δ=7.23-7.36 (m, 5H), 7.04 (d, J=8.7 Hz, 1H), 6.30(d, J=7.6 Hz, 1H), 4.92 (m, 1H), 4.56 (quintet, J=7.2 Hz, 1H), 3.56 (s,2H), 3.07 (s, 3H), 2.94 (s, 3H), 1.33-1.64 (m, 3H), 1.27 (d, J=6.9 Hz,3H), 0.94 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.5 Hz, 3H).

[1437]¹³C-nmr (CDCl₃): δ=172.0, 171.7, 170.4, 134.6, 129.2, 128.8,127.2, 48.7, 47.3, 43.5, 42.1, 36.9, 35.8, 24.6, 23.3, 21.8, 18.6.

EXAMPLE 57 Synthesis ofN,N-Dinethyl-N′-[N-(phenylacetyl)-L-alaninyl]-I-valinamide

[1438] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN,N-dimethyl-L-valinamide (prepared by coupling N-BOC-L-valine (Bachem)with dimethylamine hydrochloride (Aldrich) using General Procedure B,followed by removal of the BOC-group using General Procedure Y), thetitle compound was prepared as a solid (mp=147-149° C.). The product waspurified by extraction by EtOAc, washing with aqueous sodium carbonateand aqueous hydrochloric acid, and trituration with EtO.

[1439] NMR data was as follows:

[1440]¹H-nmr (CDCl₃): δ=7.24-7.38 (m, 5H), 6.64 (d, 1H), 6.05 (d, 1H),4.74 (dd, J=5.9, 8.9 Hz, 1H), 4.50 (quintet, J=7.1 Hz, 1H), 3.59 (s,2H), 3.08 (s, 3H), 2.96 (s, 3H), 1.97 (m, 1H), 1.28 (d, J=7.0 Hz, 3H),0.91 (d, J=6.8 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H).

[1441]¹³C-nmr (CDCl₃): δ=172.3, 171.4, 170.4, 134.6, 129.0, 128.5,126.8, 53.5, 48.5, 43.2, 37.3, 35.6, 31.2, 19.2, 18.6, 17.5.

[1442] C₁₈H₂₇N₃O₃ (MW=333.43); mass spectroscopy (MH⁺) 334.

EXAMPLE 58 Synthesis ofN-Methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1443] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN-methyl-L-phenylalaninamide (prepared by coupling N-BOC-L-phenylalanine(Bachem) with methylamine hydrochloride (Aldrich) using GeneralProcedure B, followed by removal of the BOC-group using GeneralProcedure Y), the title compound was prepared as a solid. The productwas purified by washing with aqueous sodium carbonate and aqueoushydrochloric acid.

[1444] NMR data was as follows:

[1445]¹H-nmr (DMSO-d₆): δ=8.23 (d, J=7.0 Hz, 1H), 7.95 (d, J=8.2 Hz,1H), 7.79 (d, J=4.4 Hz, 1H), 7.10-7.32 (m, 10H), 4.37 (quintet, J=5.4Hz, 1H), 4.19 (quintet, J=7.1 Hz, 1H), 3.44 (s, 2H), 2.96 (dd, J=5.5,13.7 Hz, 1H), 2.78 (dd, J=9.2, 13.7 Hz, 1H), 2.52 (d, J=4.4 Hz, 3H),1.11 (d, J=7.0 Hz, 3H).

[1446]¹³C-nmr (DMSO-d₆): δ=172.0, 171.0, 170.1, 137.8, 136.3, 129.11,129.07, 128.2, 128.1, 126.31, 126.26, 53.9, 48.5, 41.9, 37.5, 25.5,18.0.

EXAMPLE 59 Synthesis of N-Methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamide

[1447] Following General Procedure U and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN-methyl-L-valinamide (prepared by coupling N-BOC-L-valine (Bachem) withmethylamine hydrochloride (Aldrich) using General Procedure B, followedby removal of the BOC-group using General Procedure Y), the titlecompound was prepared as a solid. The product was purified by washingwith aqueous sodium carbonate and aqueous hydrochloric acid.

[1448] NMR data was as follows:

[1449]¹H-nmr (DMSO-d₆): δ=8.30 (d, J=7.6 Hz, 1H), 7.88 (d, J=4.7 Hz,1H), 7.69 (d, J=9.1 Hz, 1H), 7.17-7.32 (m, 5H), 4.34 (quintet, J=7.2 Hz,1H), 4.04 (dd, J=7.0, 8.9 Hz, 1H), 3.45 (s, 2H), 2.56 (d, J=4.6 Hz, 3H),1.87 (m, 1H), 1.18 (d, J=7.0 Hz, 3H), 0.76 (d, J=6.6 Hz, 3H), 0.75 (d,J=6.7 Hz, 3H).

[1450]¹³C-nmr (DMSO-d₆): δ=172.0, 171.1, 170.0, 136.3, 129.0, 128.1,126.3, 57.6, 48.2, 42.0, 30.6, 25.4, 19.2, 18.1, 17.9.

EXAMPLE 60 Synthesis ofN-Methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[1451] Following General Procedure U and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-methyl-L-norleucinamide (prepared by coupling N-BOC-L-norleucine(Bachem) with methylamine hydrochloride (Aldrich) using GeneralProcedure B, followed by removal of the BOC-group using GeneralProcedure Y), the title compound was prepared as a solid. The productwas purified by washing with aqueous sodium carbonate and aqueoushydrochloric acid.

[1452] NMR data was as follows:

[1453]¹H-nmr (DMSO-d₆): δ=8.37 (d, 7.1, 1H), 7.88 (d, 8.1, 1H), 7.78 (d,4.4, 1H), 7.08 (t, 9.5, 1H), 6.98 (d, 6.90, 2H), 4.27 (quintet, 7.0,1H), 4.13 (quartet, 5.5, 1H), 3.51 (s, 2H), 2.54 (d, 4.4, 3H), 1.58 (m,1H), 1.46 (m, 1H), 1.19 (m, 7H), 0.81 (t, 6.5, 3H).

[1454]¹³C-nmr (DMSO-d₆): δ=172.0, 171.9, 169.0, 162.2(dd, J=13.6, 244.0Hz), 140.7, 112.2(dd, J=8.3, 17.0 Hz), 101.9(t, J=25.5 Hz), 52.4, 48.4,41.3, 31.8, 27.4, 25.5, 21.8, 17.9, 13.8.

[1455] C₁₈H₂₅N₃O₃F₂ (MW=369.42); mass spectroscopy (MH⁺) 384.

EXAMPLE 61 Synthesis of N,N-Dimethyl-N′-[N-(3,5-difluorophenylacetyl)-alaninyl]-(S)-2-aminohexanamide

[1456] Following General Procedure U and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN,N-dimethyl-L-norleucinamide (prepared by coupling N-BOC-L-norleucine(Bachem) with dimethylamine hydrochloride (Aldrich) using GeneralProcedure B, followed by removal of the BOC-group using GeneralProcedure Y), the title compound was prepared as a solid (mp=138-140°C.). The product was purified by extraction with EtOAc and washing withaqueous sodium carbonate and aqueous hydrochloric acid. NMR data was asfollows:

[1457]¹H-nmr (CDCl₃): δ=7.11 (d, 8.1, 1H), 6.81 (m, 2H), 6.71 (m, 1H),6.60 (d, 7.6, 1H), 4.89 (q, J=5.0, 1H), 4.57 (quint, J=7.1, 1H), 3.53(s, 2H), 3.08 (s, 3H), 2.97 (s, 3H), 1.70 (m, 1H), 1.55 (m, 1H),1.20-1.38 (m, 7H), 0.85 (t, 6.9, 3H).

[1458]¹³C-nmr (CDCl₃): δ=171.6, 171.5, 168.9, 163.0 (dd, J=12.9, 247.3Hz), 138.4, 112.2 (dd, J=7.8, 17.0 Hz), 102.7 (t, J=25.0 Hz), 49.1,48.9, 42.9, 37.1, 35.8, 32.6, 27.1, 22.4, 19.1, 13.8.

[1459] C₁₉H₂₇N₃O₃F₂ (MW=383.44); mass spectroscopy (MH⁺) 384.

EXAMPLE 62 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide

[1460] Following General Procedure U and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-norleucinamide (prepared from N-BOC-L-norleucinamide (from Example D6above) using General Procedure Y), the title compound was prepared as asolid (mp=>215° C.). The product was purified by precipitation fromwater.

[1461] NMR data was as follows:

[1462]¹H-nmr (DMSO-d₆): δ=8.37 (d, 7.4, 1H), 7.83 (d, 8.0, 1H), 7.29 (s,1H), 6.95-7.14 (m, 4H), 4.29 (quintet, J=7.2, 1H), 4.14 (quartet, J=5.0,1H), 3.52 (s, 2H), 1.61 (m, 1H), 1.46 (m, 1H), 1.21 (m, 7H), 0.82 (m,3H).

[1463]¹³C-nmr (DMSO-d₆): δ=173.6, 171.9, 168.9, 162.0 (dd), 140.7, 112.2(dd, J=7.5, 16.6 Hz), 101.9 (t), 52.2, 48.3, 41.3, 31.8, 27.4, 21.8,18.0, 13.8.

[1464] C₁₇H₂₃N₃O₃F₂ (MW=355.39); mass spectroscopy (MH⁺) 356.

EXAMPLE 63 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetate

[1465] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(3-methoxyphenyl)acetate hydrochloride (prepared by theBucherer Modification of the Strecker procedure as described in J. P.Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698,Wiley, New York (1961)), the title compound was prepared as a solid(mp=163-170° C.). The reaction was monitored by tlc (Rf=0.45 in 9:1CHCl₃/MeOH) and the product was purified by silica gel chromatographyusing 97:3 CHCl₃/MeOH as the eluent.

[1466] NMR data was as follows:

[1467]¹H-nmr (CDCl₃): δ=7.27 (m, 1H), 7.18 and 7.06 (m, 1H), 6.87-6.67(m, 6H), 6.25 (m, 1H), 5.46 (m, 1H), 4.58 (m, 1H), 3.82 (s, 3H), 3.71and 3.69 (s, 3H), 3.53 and 3.48 (s, 3H), 1.39 and 1.30 (d, 3H).

[1468] C₂₁H₂₂N₂O₅F₂ (MW=420.42); mass spectroscopy (MH⁺) 421.

EXAMPLE 64 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4methoxyphenyl)acetate

[1469] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(4-methoxyphenyl)acetate hydrochloride (prepared by theBucherer Modification of the Strecker procedure as described in J. P.Greenstein et al., “The Chemistry of Amino Acids”, Vol. 1, p. 698,Wiley, New York (1961)), the title compound was prepared as a solid(mp=170-174° C.). The reaction was monitored by tlc (Rf=0.1 in 98:2CHCl₃/MeOH) and the product was purified by silica gel chromatographyusing 98:2 CHCl₃/MeOH as the eluent.

[1470] NMR data was as follows:

[1471]¹H-nmr (CDCl₃): δ=7.26 (m, 2H), 7.01-6.68 (m, 5H), 6.14 (m, 1H),5.41 (m, 1H), 4.56 (m, 1H), 3.80 (s, 3H), 3.74 and 3.71 (s, 3H), 3.54and 3.47 (s, 3H), 1.39 and 1.29 (d, 3H).

[1472] C₂₁H₂₂N₂O₅F₂ (MW=420.42); mass spectroscopy (MH⁺) 421.

EXAMPLE 65 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate

[1473] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(2-pyridyl)acetate hydrochloride (prepared as described in P.Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and referencescited therein), the title compound was prepared as a solid (mp=123-125°C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl₃/MeOH) andthe product was purified by silica gel chromatography using 95:5CHCl₃/MeOH as the eluent, followed by recrystallization fromchlorobutane.

[1474] NMR data was as follows:

[1475]¹H-nmr (CDCl₃): δ=8.53 (m, 1H), 7.70 (m, 2H), 7.48 (m, 1H), 7.27(m, 1H), 6.86 (m, 2H), 6.74 (m, 1H), 6.52 (m, 1H), 5.58 (m, 1H), 4.67(m, 1H), 4.18 (m, 2H), 3.54 and 3.50 (s, 2H), 1.48 and 1.39 (d, 3H),1.21 (m, 3H).

[1476] C₂₀H₂₁N₃O₄F₂ (MW=405.4); mass spectroscopy (MH⁺) 405.

EXAMPLE 66 Synthesis of EthylN-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-2-amino-2(4pyridyl)acetate

[1477] Following General Procedure C and usingN-(3,5difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(4-pyridyl)acetate hydrochloride (prepared as described in P.Kolar et al., J. Heterocyclic Chem., 28, 1715 (1991) and referencescited therein), the title compound was prepared as a solid (mp=175-181°C.). The reaction was monitored by tlc (Rf=0.1 in 98:2 CHCl₃/MeOH) andthe product was purified by silica gel chromatography using 95:5CHCl₃/MeOH as the eluent, followed by recrystallization fromchlorobutane.

[1478] NMR data was as follows:

[1479]¹H-nmr (CDCl₃): δ=8.59 (m, 2H), 7.39 (m, 1H), 7.26 (m, 2H), 6.80(m, 3H), 6.21 (m, 1H), 5.51 (m, 1H), 4.62 (m, 1H), 4.21 (m, 2H), 3.57and 3.51 (s, 2H), 1.38 (m, 3H), 1.23 (m, 3H).

[1480] C₂₀H₂₁N₃O₄F₂ (MW=405.4); mass spectroscopy (MH⁺) 405.

EXAMPLE 67 Synthesis ofN-[N-(Cyclohexylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1481] Following General Procedure U and using cyclohexylacetic acid(Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared bycoupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl esterhydrochloride (Bachem) using General Procedure U, followed by removal ofthe BOC-group using General Procedure Y), the title compound wasprepared as a solid (mp=156 158° C.). The reaction was monitored by tlc(Rf=0.25 in 1:1 EtOAc/hexanes).

[1482] NMR data was as follows:

[1483]¹H-nmr (CDCl₃): δ=0.95 (m, 2H), 1.10-1.38 (m, 3H), 1.33 (d, J=7.0Hz, 3H), 1.60-1.86 (m, 6H), 2.02 (d, J=7.5 Hz, 2H), 3.10 (m, 2H), 3.71(s, 3H), 4.49 (m, 1H), 4.81 (m, 1H), 6.10 (d, J=7.3 Hz, 1H), 6.65 (d,J=7.7 Hz, 1H), 7.11 (m, 2H), 7.26 (m, 3H).

[1484]¹³ C-nmr (CDCl₃): δ=18.4, 26.0, 26.1, 33.0, 33.1, 35.3, 37.8,44.5, 48.5, 52.4, 53.3, 127.1, 128.6, 129.2, 135.6, 171.6, 172.0, 172.2.

[1485] C₂₁H₃₀N₂O₄ (MW=374.48); mass spectroscopy (MH⁺) 375.

EXAMPLE 68 Synthesis ofN-[N-(Cyclopentylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1486] Following General Procedure U and using cyclopentylacetic acid(Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared bycoupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl esterhydrochloride (Bachem) using General Procedure U, followed by removal ofthe BOC-group using General Procedure Y), the title compound wasprepared as a solid (mp=137-139° C.). The reaction was monitored by tlc(Rf=0.23 in 1:1 EtOAc/hexanes).

[1487] NMR data was as follows:

[1488]¹H-nmr (CDCl₃): δ=1.13 (m, 2H), 1.33 (d, J=7.0 Hz, 3H), 1.58 (m,4H), 1.80 (m, 2H), 2.17 (m, 3H), 3.10 (m, 2H), 3.71 (s, 3H), 4.50 (m,1H), 4.83 (m, 1H), 6.12 (d, J=7.4 Hz, 1H), 6.69 (d, J=7.7 Hz, 1H), 7.2(m, 2H), 7.25 (m, 3H).

[1489]¹³C-nmr (CDCl₃): δ=18.3, 24.9, 32.4, 32.5, 37.0, 37.7, 42.7, 48.4,52.3, 53.3, 127.1, 128.5, 129.2, 135.7, 171.6, 172.0, 172.6.

[1490] C₂₀H₂₈N₂O₄ (MW=360.46); mass spectroscopy (MH⁺) 361.

EXAMPLE 69 Synthesis ofN-[N-(Cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1491] Following General Procedure U and using cyclohex-1-enylaceticacid (Alfa) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared bycoupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl esterhydrochloride (Bachem) using General Procedure U, followed by removal ofthe BOC-group using General Procedure Y), the title compound wasprepared as a solid (mp=139-142° C.). The reaction was monitored by tlc(Rf 0.27 in 1:1 EtOAc/hexanes).

[1492] NMR data was as follows:

[1493]¹H-nmr (CDCl₃): δ=1.31 (d, J=7.0 Hz, 3H), 1.58 (m, 4H), 1.89 (m,2H), 2.04 (br s, 2H), 2.83 (s, 2H), 3.00-3.20 (m, 2H), 3.71 (s, 3H),4.47 (m, 1H), 4.81 (m, 1H), 5.60 (s, 1H), 6.26 (d, J=7.3 Hz, 1H), 6.67(d, J=7.7 Hz, 1H), 7.11 (m, 2H), 7.26 (m, 3H).

[1494]¹³C-nmr (CDCl₃): δ=18.1, 21.9, 22.7, 25.3, 28.3, 37.7, 46.0, 48.4,52.3, 53.3, 127.1, 127.2, 128.5, 129.1, 132.2, 135.7, 171.0, 171.6,171.8.

[1495] C₂₁H₂₈N₂O₄ (MW=372.47); mass spectroscopy (MH⁺) 373.

EXAMPLE 70 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxylate

[1496] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 1-aminocyclopropane-1-carboxylate hydrochloride (Sigma), thetitle compound was prepared as a solid. The reaction was monitored bytlc (Rf=0.3 in 95:5 CHCl₃/MeOH) and the product was purified by silicagel chromatography using 97:3 CHCl/MeOH as the eluent.

[1497] NMR data was as follows:

[1498]¹H-nmr (CDCl₃): δ=6.96 (bs, 1H), 6.82 (m, 2H), 6.69 (m, 1H), 6.48(d, 1H), 4.50 (m, 1H), 3.67 (s, 3H), 3.54 (s, 2H), 1.58 (m, 2H), 1.40(d, 2H), 1.12 (m, 2H).

[1499] Optical Rotation: [α]₂₃=−18° (c 1, MeOH).

EXAMPLE 71 Synthesis ofN-2-(N,N-Dimethylamino)ethyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Lalaninamide

[1500] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and N,N,N′-trimethylethylenediamine (Aldrich), the title compoundwas prepared as a solid.

[1501] NMR data was as follows:

[1502]¹H-nmr (DMSO-d₆): δ=8.37 (m, 2H), 8.19 (d, 1H), 8.08 (d, 2H), 7.10(m, 1H), 6.99 (m, 2H), 4.67 (m, 1H), 4.30 (m, 1H), 3.52 (s, 2H), 3.01and 2.86 (s, 3H), 2.47 (t, 1H), 2.31 (t, 1H), 2.15 (s, 6H), 1.19 (m,6H).

[1503] Optical Rotation: [α]₂₃=−85° (c 1, MeOH).

[1504] C₁₉H₂₈N₄O₃F₂ (MW=398.45); mass spectroscopy (MH⁺) 398.

EXAMPLE 72 Synthesis ofN-[N-(Cyclopropylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1505] Following General Procedure U and using cyclopropylacetic acid(Lancaster) and N-(L-alaninyl)-L-phenylalanine methyl ester (prepared bycoupling N-BOC-L-alanine (Bachem) with L-phenylalanine methyl esterhydrochloride (Bachem) using General Procedure U, followed by removal ofthe BOC-group using General Procedure Y), the title compound wasprepared as a solid (mp=128-131° C.). The reaction was monitored by tlc(Rf=0.14 in 1:1 EtOAc/hexanes).

[1506] NMR data was as follows:

[1507]¹H-nmr (CDCl₃): δ=0.17 (m, 2H), 0.59 (m, 2H), 0.92 (m, 1H), 1.35(d, J=7.0 Hz, 3H), 2.11 (m, 2H), 3.05 (dd, J=6.7, 13.9 Hz, 1H), 3.16(dd, J=5.5, 13.9 Hz, 1H), 3.73 (s, 3H), 4.52 (m, 1H), 4.82 (m, 1H), 6.47(d, J=7.1 Hz, 1H), 6.70 (d, J=7.5 Hz, 1H), 7.12 (m, 2H), 7.28 (m, 3H).

[1508]¹³C-nmr (CDCl₃): S=4.6, 6.9, 18.2, 37.7, 41.2, 48.4, 52.4, 53.2,127.1, 128.5, 129.2, 135.7, 171.7, 171.9, 172.3.

[1509] C₁₈H₂₄N₂O₄ (MW=332.40); mass spectroscopy (MH⁺) 333.

EXAMPLE 73 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]glycine Benzyl Ester

[1510] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andglycine benzyl ester (prepared from N-BOC-glycine (Bachem) and benzylalcohol (Aldrich) using General Procedure X, followed by removal of theBOC-group using General Procedure Y), the title compound was prepared asa solid (mp=167.5° C.). The reaction was monitored by tlc (Rf=0.35 in 2%MeOH/CH₂Cl) and the product was purified by flash chromatography using2% MeOH/CH₂Cl₂ as the eluent.

[1511] NMR data was as follows:

[1512]¹H-nmr (CDCl₃): δ=7.12 (m, 5H), 6.71 (m, 3H), 6.60 (m, 2H), 4.95(s, 2H), 4.18 (q, 1H), 3.76 (dd, 2H), 3.35 (s, 2H), 1.13 (d, 3H).

[1513]¹³C-nmr (CDCl₃): δ=176.0, 172.9, 171.5, 166.46, 163.30, 141.54,137.70, 130.11, 129.88, 113.98, 113.87, 113.75, 113.64, 103.89, 103.55,103.21, 68.44, 50.93, 43.25, 42.61, 18.65.

[1514] C₂₀H₂₀N₂O₄F₂ (MW=390.39); mass spectroscopy (MH⁺) 391.

EXAMPLE 74 Synthesis of N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alanineEthyl Ester

[1515] Following General Procedure C and usingN-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid (Aldrich)and L-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by hydrolysis using General Procedure AF) andL-alanine ethyl ester hydrochloride (Sigma), the title compound wasprepared as a solid (mp=198-201° C.). The reaction was monitored by tlc(Rf=0.3 in 1:1 EtOAc/hexanes) and the product was purified by silica gelchromatography using 5 % MeOH/CHCl₃ as the eluent, followed byrerystallization from EtOAc.

[1516] NMR data was as follows:

[1517]¹H-nmr (DMSO-d₆)(1:5 mixture of diastereomers): δ=1.25 and 1.30(two d, 3H), 5.57 (d, 1H), 5.60 (d, 1H).

[1518] C₁₈H₂₆N₂O₄ (MW=334.42); mass spectroscopy (MH⁺) 335.

EXAMPLE 75 Synthesis ofN-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1519] Following General Procedure Z and usingN-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (fromExample D8 above) and L-phenylalanine methyl ester hydrochloride(Sigma), the title compound was prepared as a solid (mp=154-158° C.).The reaction was monitored by tlc (Rf=0.3 in 1:1 EtOAc/hexanes) and theproduct was purified by silica gel chromatography using 50-100%EtOAc/hexanes as the eluent.

[1520] NMR data was as follows:

[1521] H-nmr (DMSO-d₆)(1:3 mixture of diastereomers): δ=1.00 and 1.18(two d, 3H), 2.96 (m, 2H).

[1522] C₂₁H₂₃N₃O₆ (MW=413.43); mass spectroscopy (MH⁺) 413.

EXAMPLE 76 Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-alanineEthyl Ester

[1523] Following General Procedure Z and usingN-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (fromExample D8 above) and L-alanine ethyl ester hydrochloride (Sigma), thetitle compound was prepared as a solid (mp=193-195° C.). The reactionwas monitored by tlc (Rf=0.4 in EtOAc) and the product was purified bysilica gel chromatography using EtOAc as the eluent.

[1524] NMR data was as follows:

[1525]¹H-nmr (DMSO-d₆): δ=1.20 (m, 9H), 3.65 (s, 2H); 4.05 (m, 2H).

[1526] Optical Rotation: [α]₂₀=−27.3@589nm, (c=1.02, DMSO).

[1527] C₁₆H₂₁N₃O₆ (MW=351.36); mass spectroscopy (MH⁺) 352.

EXAMPLE 77 Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninylglycineEthyl Ester

[1528] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylaceticacid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) usingGeneral Procedure C, followed by hydrolysis using General Procedure AF)and glycine ethyl ester hydrochloride (Sigma), the title compound wasprepared as a solid (mp=164-165° C.). The product was purified by silicagel chromatography using EtOAc as the eluent, followed byrecrystallization from EtOAc.

[1529] NMR data was as follows:

[1530] H-nmr (DMSO-d₆): δ=1.20 (m, 6H), 4.08 (q, 2H); 4.32 (m, 1H).

[1531] Optical Rotation: [α]₂₀=−25@589 nm, (c=1.00, DMSO).

[1532] C₁₅H₁₉N₃O₆ (MW=337.33); mass spectroscopy (MH⁺) 338.

EXAMPLE 78 Synthesis of N-Hydroxy-N′-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamide

[1533] Following General Procedure Z and usingN-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (fromExample D8 above) and D,L-threonine hydroxamate (Sigma), the titlecompound was prepared as a solid (mp=180-183° C.). The reaction wasmonitored by tlc(Rf=0.25 in 15% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 15% MeOH/CHCl₃ as the eluent,followed by recrystallization from EtOAc.

[1534] NMR data was as follows:

[1535]¹H-nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=1.22 (m, 3H);0.98 (m, 3H).

[1536] C₁₅H₂₀N₄O₇ (MW=368.35); mass spectroscopy (MH⁺) 368.

EXAMPLE 79 Synthesis of N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alanineiso-butyl Ester

[1537] Following General Procedure C and usingN-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid (Aldrich)and L-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by hydrolysis using General Procedure AF) andL-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-alanine(Sigma) and 2-methyl-l-propanol (Aldrich) using General Procedure C(with catalystic DMAP), followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=181-186° C). The reaction was monitored by tlc (Rf=0.4 in 1:1EtOAc/hexanes) and the product was purified by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluent.

[1538] NMR data was as follows:

[1539]¹H-nmr (DMSO-d₆): δ=1.31 (d, 3H); 5.59 (d, 1H).

[1540] Optical Rotation: [α]₂₀=+19.0@589 nm, (c=1.03, DMSO).

[1541] C₂₀H₂₉N₂O₄ (MW=362.47); mass spectroscopy (MH⁺) 363.

EXAMPLE 80 Synthesis of MethylN-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino3-(3-hydroxyphenyl)propionate

[1542] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylaceticacid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) usingGeneral Procedure C, followed by hydrolysis using General Procedure AF)and methyl 2-amino-3-(3-hydroxyphenyl)propionate (prepared from2-amino-3-(3-hydroxyphenyl)propionate (Biosynth AG, Switzerland) andmethanol using General Procedure H), the title compound was prepared asa solid (mp=155-159° C.). The reaction was monitored by tlc (Rf=0.4 inEtOAc) and the product was purified by silica gel chromatography usingEtOAc as the eluent.

[1543] NMR data was as follows:

[1544]¹H-nmr (DMSO-d₆)(1: 1 mixture of diastereomers): δ=1.02 and 1.20(two d, 3H); 3.62 (2 s, 3H).

[1545] C₂₁H₂₃N₂O₇ (MW=429.43); mass spectroscopy (MH⁺) 429.

EXAMPLE 81 Synthesis ofN-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-tyrosine Ethyl Ester

[1546] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylaceticacid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) usingGeneral Procedure C, followed by hydrolysis using General Procedure AF)and L-tyrosine ethyl ester (Sigma), the title compound was prepared as asolid (mp=117-119° C.). The reaction was monitored by tlc (Rf=0.5 inEtOAc) and the product was purified by silica gel chromatography usingEtOAc as the eluent.

[1547] NMR data was as follows:

[1548]¹H-nmr (DMSO-d₆): δ=1.07 (t, 3H); 1.20 (d, 3H); 9.23 (s, 1H).

[1549] Optical Rotation: [α]₂₀=−13.1@589 nm, (c=1.08, DMSO).

[1550] C₂₂H₂₅N₃O₇ (MW=443.46); mass spectroscopy (MH⁺) 443/444.

EXAMPLE 82 Synthesis of N-[N-(Isovaleryl)-L-isoleucinyl]-L-alanineiso-butyl Ester

[1551] Following General Procedure C and usingN-(isovaleryl)-L-isoleucine (prepared from isovaleric acid (Aldrich) andL-isoleucine methyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by hydrolysis using General Procedure AF) andL-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-alanine(Sigma) and 2-methyl-1-propanol (Aldrich) using General Procedure C(with catalystic DMAP), followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=142-146° C.). The reaction was monitored by tlc (Rf=0.4 in 1:1EtOAc/hexanes) and the product was purified by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluent.

[1552] NMR data was as follows:

[1553]¹H-nmr (DMSO-d₆)(1:4 mixture of diastereomers): δ=1.26 (d, 3H),7.70, 7.80 (doublets, 1H); 8.30, 8.40 (doublets, 1H).

[1554] C₁₈H₃₄N₂O₄ (MW=342.48); mass spectroscopy (MH⁺) 343.

EXAMPLE 83 Step A—Synthesis ofN-[N-[N-(teit-Butoxycarbonyl)-L-valinyl]-D,L-phenylglycinyl]-L-alanineiso-butyl Ester

[1555] Following General Procedure A and usingN-[N-BOC-L-valinyl]-D,L-phenylglycine (prepared by couplingN-BOC-L-valine (Bachem) and L-phenylglycine methyl ester hydrochloride(Sigma) using General Procedure C, followed by hydrolysis of the methylester using General Procedure AF) and L-alanine iso-butyl esterhydrochloride (prepared from N-BOC-L-alanine (Sigma) and2-methyl-l-propanol (Aldrich) using General Procedure C (with catalyticDMAP), followed by removal of the BOC-group using General Procedure P),the title compound was prepared. The reaction was monitored by tlc(Rf=0.3 in 5 % MeOH/CH₂Cl₂) and the product was purified by silica gelchromatography using 5% MeOH/CH₂Cl₂ as the eluent.

[1556] NMR data was as follows:

[1557]¹H-nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=1.25 (d, 3H);5.58 (d, 1H).

[1558] C₂₅H₃₉N₃O₆ (MW=477.61); mass spectroscopy (MH⁺) 478.

Step B—Synthesis of N-[N-(L-Valinyl)-L-phenylglycinyl]L-alanineiso-butyl Ester Hydrochloride

[1559] Following General Procedure P and using the product from Exarnple83—Step A above, the title compound was prepared as a solid (mp=225-232°C.). The product was purified by trituration in EtO.

[1560] NMR data was as follows:

[1561]¹H-nmr (DMSO-d₆)(1:2 mixture of diastereomers): δ=1.26, 1.32(doublets, 3H); 5.60, 5.65 (doulets, 1H).

[1562] C₂₀H₃₂N₃O₄Cl (MW=413.94); mass spectroscopy (MH⁺) 378 (freebase).

Step C—Synthesis ofN-[N-[N-(Isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanine isobutylEster

[1563] Following General Procedure C and using isovaleric acid (Aldrich)and the product from Example 83 - Step B above, the title compound wasprepared as a solid (mp=217-221° C.). The reaction was monitored by tlc(Rf=0.25 in 5% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 5% MeOH/CHCl₃) as the eluent.

[1564] NMR data was as follows:

[1565] H-nmr (DMSO-d₆)(1:3 mixture of diastereomers): δ=5.52, 5.58(doublets, 1H).

[1566] C₂₅H₃₉N₃O₅ (MW=461.60); mass spectroscopy (MH⁺) 462.

EXAMPLE 84 Synthesis of N-[N-(Isovaleryl)-L-phenylalaninyl]-L-alanineiso-butyl Ester

[1567] Following General Procedure C and using isovaleric acid (Aldrich)and N-(L-phenylalaninyl)-L-alanine iso-butyl ester hydrochloride(prepared from N-BOC-L-phenylalanine (Sigma) and L-alanine iso-butylester hydrochloride (prepared as described in Example 83A above) usingGeneral Procedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=135-138°C.). The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl₃) and theproduct was purified by silica gel chromatography using 3 % MeOH/CHCl₃as the eluent.

[1568] NMR data was as follows:

[1569]¹H-nmr (DMSO-d₆): δ=0.75 (d, 3H), 0.84 (d, 3H); 0.90 (d, 6H); 1.33(d, 3H).

[1570] Optical Rotation: [α]₂₀=+4.71°@589 nm, (c=1.02, DMSO).

[1571] C₂₁H₃₂N₂O₄ (MW=376.50); mass spectroscopy (MH⁺) 376.

EXAMPLE 85 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alanine Ethyl Ester

[1572] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and L-alanine ethyl ester hydrochloride (Sigma), thetitle compound was prepared as a solid (mp=197-199° C.). The reactionwas monitored by tlc (Rf=0.6 in EtOAc) and the product was purified frombi-products by silica gel chromatography using EtOAc as the eluent,followed by recrystallization from EtOAc.

[1573] NMR data was as follows:

[1574]¹H-nmr (DMSO-d₆): δ=1.22 (m, 9H); 3.52 (s, 2H).

[1575] Optical Rotation: [α]₂₀=−76.10°@589 nm, (c=1.01, DMSO).

[1576] C₁₆H₂₀N₂O₄F₂ (MW=342.34); mass spectroscopy (MH⁺) 343.

EXAMPLE 86 Synthesis of Ethyl1-[N-(3-Nitrophenylacetyl)-L-alaninyl]indoline-(S)-2-carboxylate

[1577] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylaceticacid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) usingGeneral Procedure C, followed by hydrolysis using General Procedure AF)and ethyl (S)-indoline-2-carboxylate (prepared from(S)-indoline-2-carboxylic acid (Aldrich) and ethanol using GeneralProcedure H), the title compound was prepared as a solid. The reactionwas monitored by tlc (Rf=0.4 in 2:1 EtOAc/hexanes) and the product waspurified by silica gel chromatography using 2:1 EtOAc/hexanes as theeluent.

[1578] NMR data was as follows:

[1579]¹H-nmr (DMSO-d₆)(1:2 mixture of diastereomers): δ=1.05, 1.17(triplets, 3H); 1.29, 1.39 (doublets, 3H).

[1580] C₂₂H₂₃N₃O₆ (MW=425.44); mass spectroscopy (MH⁺) 425.

EXAMPLE 87 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1581] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-alaninamide hydrochloride (Sigma), the title compound was prepared asa solid (mp=285-288° C.). The reaction was monitored by tlc (Rf=0.35 in10% MeOHICHCl₃) and the product was purified by silica gelchromatography using 10% MeOH/CHCl₃ as the eluent, followed byrecrystallization from EtOH.

[1582] NMR data was as follows:

[1583]¹H-nmr (DMSO-d₆): δ=1.21 (m, 6H); 7.95 (d, 1H); 8.37 (d, 1H).

[1584] Optical Rotation: [C]₂₀=−26.84°@589 nm, (c=1.01, DMSO).

[1585] C₁₄H₁₇N₃O₃F₂ (MW=313.31); mass spectroscopy (MH⁺) 314.

EXAMPLE 88 Synthesis ofN-Methoxy-N-methyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide

[1586] Following General Procedure C and usingN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared fromN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from Example74 above) using General Procedure AF) and N,O-dimethylhydroxylamine(Aldrich), the title compound was prepared as a solid. The reaction wasmonitored by tlc (Rf=0.6 in EtOAc) and the product was purified bysilica gel chromatography using EtOAc as the eluent.

[1587] NMR data was as follows:

[1588]¹H-nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=3.67, 3.73(singlets, 3H), 5.62 (m, 1H).

[1589] C₁₈H₂₇N₃O₄ (MW=349.43); mass spectroscopy (MH⁺) 350.

EXAMPLE 89 Synthesis ofN-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1590] Following General Procedure C and usingN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared fromN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (fromExample 85 above) using General Procedure AF) and iso-butylamine(Aldrich), the tide compound was prepared as a solid (mp=258-260° C.).The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃) and theproduct was purified by silica gel chromatography using 10% MeOH/CHCl₃as the eluent.

[1591] NMR data was as follows:

[1592]¹H-nmr (DMSO-d₆): δ=0.80 (d, 6H); 1.20 (m, 6H).

[1593] Optical Rotation: [α]₂₀=−30.4°@589 nm, (c=1.01, DMSO).

[1594] C₁₈H₂₅N₃O₃F₂ (MW=369.41); mass spectroscopy (MH⁺) 369.

EXAMPLE 90 Synthesis ofN,N-Di-n-propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1595] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared fromN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (fromExample 85 above) and di-n-propylamine (Aldrich), the title compound wasprepared as a solid (mp=137-146° C.). The reaction was monitored by tlc(Rf=0.5 in 10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 5% MeOH/CHCl₃ as the eluent.

[1596] NMR data was as follows:

[1597]¹H-nmr (DMSO-d₆)(1:2 mixture of diastereomers): δ=3.50 (s, 2H),4.30 (m, 1H), 4.63 (m, 1H).

[1598] C₂₀H₂₉N₃O₃F₂ (MW=397.46); mass spectroscopy (MH⁺) 397.

EXAMPLE 91 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-valinamide

[1599] Following General Procedure C and usingN-(3,5difluorophenylacetyl)-L-alanine (from Example B2 above) andL-valinamide hydrochloride (Sigma), the title compound was prepared as asolid. The reaction was monitored by tlc (Rf=0.3 in 10% MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 10%MeOH/CHCl₃ as the eluent.

[1600] NMR data was as follows:

[1601]¹H-nmr (DMSO-d₆)(1:4 mixture of diastereomers): δ=1.22 (m, 3H);1.97 (m, 1H).

[1602] C₁₆H₂₁N₃O₃F₂ (MW=341.36) mass spectroscopy (MH⁺) 342.

EXAMPLE 92 Synthesis ofN-(4Nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamnide

[1603] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(4-nitrophenyl)-L-alaninamide hydrochloride (Fluka), the titlecompound was prepared as a solid (mp=242-244° C.). The reaction wasmonitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 10% MeOH/CHCl₃ as the eluent,followed by recrystallization from acetonitrile.

[1604] NMR data was as follows:

[1605]¹H-nmr (DMSO-d₆): δ=1.24 (d, 3H); 1.33 (d, 3H).

[1606] Optical Rotation: [α]₂₀=−5.18°@589 nm, (c=1.00, DMSO).

[1607] C₂₀H₂₀N₄O₅F₂ (MW=434.40); mass spectroscopy (MH⁺) 434.

EXAMPLE 93 Synthesis ofN′-[N-[N-(Isovaleryl)-L=phenylglycinyl]-L-alaninyl]-L-phenylalaninamide

[1608] Following General Procedure C and usingN-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid (Aldrich)and L-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by hydrolysis using General Procedure AF) andN′-(-alaninyl)-L-phenylalaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and L-phenylalaninamide (Sigma) using GeneralProcedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=272-276°C.). The reaction was monitored by tlc (Rf=0.25 in 10% MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 10%MeOH/CHCl₃ as the eluent.

[1609] NMR data was as follows:

[1610]¹H-nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=1.07, 1.17(doublets, 3H); 5.40, 5.52 (doublets, 1H).

[1611] C₂₅H₃₂N₄O₄ (MW=452.55); mass spectroscopy (MH⁺) 453.

EXAMPLE 94 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1612] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and N-(L-alaninyl)-L-phenylalanine methyl esterhydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninemethyl ester hydrochloride (Sigma) using General Procedure C, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=173-175° C.). The reaction wasmonitored by tlc (Rf=0.6 in 10% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 4% MeOH/CHCl₃ as the eluent, followedby recrystallization from 1-chlorobutane/acetonitrile.

[1613] NMR data was as follows:

[1614]¹H-nmr (DMSO-d₆): δ=1.17 (d, 3H); 3.48 (s, 2H).

[1615] Optical Rotation: [α₂₀=−32.47°@589 nm, (c=1.01, MeOH).

[1616] C₂₁H₂₂N₂O₄F₂ (MW=404.41); mass spectroscopy (MH⁺) 404.

EXAMPLE 95 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalaniniaide

[1617] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and N′-(L-alaninyl)-L-phenylalaninamide hydrochloride(prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninamide (Sigma)using General Procedure C, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=252-253° C.). The reaction was monitored by tlc(Rf=0.5 in 15%MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 15% MeOH/CHCl₃ as the eluent, followed by recrystallization fromEtOH.

[1618] NMR data was as follows:

[1619]¹H-nmr (DMSO-d₆): δ=1.15 (d, 3H); 3.51 (s, 2H).

[1620] Optical Rotation: [α]₂₀=−24.4°@nm, (c=1.01, DMSO).

[1621] C₂₀H₂₁N₃O₃F₂ (MW=389.41); mass spectroscopy (MH⁺) 389.

EXAMPLE 96 Synthesis ofN-iso-butyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamnide

[1622] Following General Procedure C and usingN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared fromN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from Example74 above) using General Procedure AF) and iso-butylamine (Aldrich), thetitde compound was prepared as a solid (mp=227-232° C.). The reactionwas monitored by tlc (Rf=0.3 in 5% MeOH/CHCl₃) and the product waspurified by silica gel chromatography using 5% MeOH/CHCl₃ as the eluent,followed by recrystallization from acetonitrile.

[1623] NMR data was as follows:

[1624]¹H-nmr (DMSO-d₆)(1:4 mixture of diastereomers): δ=1.58 (m, 1H);1.95 (m, 1H); 5.55 (d, 1H).

[1625] C₂₀H₃₁N₃O₃ (MW=361.48); mass spectroscopy (MH⁺) 361.

EXAMPLE 97 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaniinyl]-L-phenylalaninamide

[1626] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (preparedfrom N-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methylester (from Example 94) using General Procedure AF) and2-methoxyethylamine (Aldrich), the title compound was prepared as asolid (mp=206-208° C.). The reaction was monitored by tlc (Rf=0.3 in 10%MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 10% MeOH/CHCl₃ as the eluent, followed by recrystallization from1-chlorobutane/acetonitrile.

[1627] NMR data was as follows:

[1628] H-nmr (DMSO-d₆): δ=1.14 (d, 3H); 4.22 (m, 1H); 4.45 (m, 1H).

[1629] Optical Rotation: [α]₂₀=−25°@589 nm, (c=1.00, DMSO).

[1630] C₂₃H₂₇N₃O₄F₂ (MW=447.49); mass spectroscopy (MH⁺) 447.

EXAMPLE 98 Synthesis ofN-(4Nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1631] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared fromN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (fromExample 85 above) using General Procedure AF) and 4-nitrobenzylamine(Aldrich), the title compound was prepared as a solid (mp=257-259° C.).The reaction was monitored,by tlc (Rf=0.4 in 10% MeOH/CHCl₃) and theproduct was purified by silica gel chromatography using 10% MeOH/CHCl₃as the eluent, followed by recrystallization from EtOH/acetonitrile.

[1632] NMR data was as follows:

[1633]¹H-nmr (DMSO-d₆): δ=3.53 (s, 2H); 4.39 (d, 2H).

[1634] Optical Rotation: [α]₂₀=−29.3°@589 nm, (c=1.00, DMSO).

[1635] C₂₁H₂₂N₄O₅F₂ (MW=448.43); mass spectroscopy (MH⁺) 448.

EXAMPLE 99 Synthesis ofN-(4Nitrophenyl)-N′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamide

[1636] Following General Procedure C and usingN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine (prepared fromN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl ester (from Example74 above) using General Procedure AF) andN-(4-nitrophenyl)-L-alaninamide hydrochloride (Fluka), the titlecompound was prepared as a solid (mp=255-257° C.). The reaction wasmonitored by tlc (Rf=0.5 in 10% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 10% MeOH/CHCl₃ as the eluent,followed by recrystallization from 1-chlorobutane/acetonitrile.

[1637] NMR data was as follows:

[1638]¹H-nmr (DMSO-d₆)(1:2 mixture of diastereomers): δ=5.45, 5.55(doublets, 1H); 10.20, 10.54 (singlets, 1H).

[1639] C₂₅H₃₁N₄O₆ (MW=497.56); mass spectroscopy (MH⁺) 497.

EXAMPLE 100 Synthesis ofN-(4Nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninaimide

[1640] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(4-nitrophenyl)-L-phenylalaninamide hydrochloride (Lancaster), thetitle compound was prepared as a solid (mp=253-254° C.). The reactionwas monitored by tlc (Rf=0.5 in 10% MeOHICHCl₃) and the product waspurified by silica gel chromatography using 8% MeOH/CHCl₃ as the eluent.

[1641] NMR data was as follows:

[1642]¹H-nmr (DMSO-d₆): δ=1.17 (d, 3H); 10.52 (s, 1H).

[1643] Optical Rotation: [α]₂₀=+40.6°@589 nm, (c=1.00, DMSO).

[1644] C₂₆H₂₄N₄O₅F₂ (MW=510.50); mass spectroscopy (MH⁺) 510.

EXAMPLE 101 Synthesis ofN-Benzyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninide

[1645] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (prepared fromN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (fromExample 85 above) using General Procedure AF) and N-benzyl-N-methylamine(Aldrich), the title compound was prepared as a solid (mp=167-169° C.).The reaction was monitored by tlc (Rf=0.4 in 5% MeOHICHCl₃) and theproduct was purified by silica gel chromatography using 5 % MeOH/CHCl₃as the eluent, followed by recrystallization from acetonitrile.

[1646] NMR data was as follows:

[1647]¹H-nmr (DMSO-d₆)(1:3 mixture of diastereomers): δ=3.52 (singlets,2H); 2.95 (s, 2H).

[1648] Optical Rotation: [α]₂₀=−55.8°@589 nm, (c=1.01, DMSO).

[1649] C₂₂H₂₅N₃O₃F₂ (MW=417.45); mass spectroscopy (MH⁺) 417.

EXAMPLE 102 Synthesis ofN-(3,5-Difluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1650] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(3,5-difluorobenzyl)-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and 3,5-difluorobenzylamine (Lancaster) usingGeneral Procedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=267-269°C.). The reaction was monitored by tlc (Rf=0.25 in 10% MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 10%MeOH/CHCl₃ as the eluent, followed by recrystallization fromacetonitrile.

[1651] NMR data was as follows:

[1652]¹H-nmr (DMSO-d₆): δ=1.21 (d, 3H), 1.24 (d, 3H).

[1653] Optical Rotation: [α]₂₀=+26.9°@589 nm, (c=1.01, DMSO).

[1654] C₂₁H₂₁N₃O₃F₄ (MW=439.41); mass spectroscopy (MH⁺) 439.

EXAMPLE 103 Synthesis ofN-(3-Nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1655] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(3-nitrobenzyl)-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and 3-nitrobenzylamine hydrochloride (Aldrich)using General Procedure C, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=245-247° C.). The reaction was monitored by tlc (Rf=0.4 in 10%MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 10% MeOH/CHCl₃ as the eluent, followed by recrystallization fromacetonitrile.

[1656] NMR data was as follows:

[1657]¹H-nmr (DMSO-d₆): δ=1.21 (d, 3H); 1.25 (d, 3H).

[1658] Optical Rotation: [α]₂₀=−32.8°@589 nm, (c=1.00, DMSO).

[1659] C₂₁H₂₂N₄O₅F₂ (MW=448.43); mass spectroscopy (MH⁺) 449.

EXAMPLE 104 Synthesis ofN-Benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1660] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-benzyl-L-alaninamide hydrochloride (prepared from N-BOC-L-alanine(Sigma) and benzylamine (Aldrich) using General Procedure C, followed byremoval of the BOC-group using General Procedure P), the title compoundwas prepared as a solid (mp=260-262° C.). The reaction was monitored bytlc (Rf=0.3 in 10% MeOH/CHCl₃) and the product was purified by silicagel chromatography using 10% MeOH/CHCl₃ as S the eluent, followed byrecrystallization from acetonitrile.

[1661] NMR data was as follows:

[1662]¹H-nmr (DMSO-d₆): δ=1.20 (d, 3H); 1.24 (d, 3H).

[1663] Optical Rotation: [α]₂₀=−29.30°@589 nm, (c=1.03, DMSO).

[1664] C₂₁H₂₃N₃O₃F₂ (MW=403.43); mass spectroscopy (MH⁺) 403.

EXAMPLE 105 Synthesis of N- (4Nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide

[1665] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (preparedfrom N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methylester (from Example 94) using General Procedure AF) and4-nitrobenzylamine hydrochloride (Aldrich), the title compound wasprepared as a solid (mp=248-250° C.). The reaction was monitored by tlc(Rf=0.4 in 12% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 12% MeOH/CHCl₃ as the eluent, followed byrecrystallization from acetonitrile.

[1666] NMR data was as follows:

[1667]¹H-nmr (DMSO-d₆): δ=1.15 (d, 3H); 7.35 (d, 2H); 8.12 (d, 2H).

[1668] Optical Rotation: [α]₂₀=−27.6°@589 nm (c=1.01, DMSO).

[1669] C₂₇H₂₆N₄O₅F₂ (MW=524.52); mass spectroscopy (MH⁺) 524.

EXAMPLE 106 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tryptophan Methyl Ester

[1670] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-tryptophan methyl ester hydrochloride (Sigma), the title compound wasprepared as a solid (mp=191-193° C.). The reaction was monitored by tlc(Rf=0.4 in 10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 5 % MeOH/CHCl₃ as the eluent, followed byrecrystallization from l-chlorobutanelacetonitrile.

[1671] NMR data was as follows:

[1672]¹H-nmr (DMSO-d₆): δ=1.20 (d, 3H); 3.55 (s, 3H).

[1673] Optical Rotation: [α]₂₀=−8.82°@589 nm (c=1.02, DMSO).

[1674] C₂₃H₂₃N₃O₄F₂ (MW=443.45); mass spectroscopy (MH⁺) 443.

EXAMPLE 107 Synthesis ofN-(4Methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1675] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(4-methoxybenzyl)-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and 4-methoxybenzylamine hydrochloride (Aldrich)using General Procedure C, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=234-236° C.). The reaction was monitored by tlc (Rf=0.3 in 10%MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 10% MeOH/CHCl₃ as the eluent, followed by recrystallization fromEtOH/acetonitrile.

[1676] NMR data was as follows:

[1677]¹H-nmr (DMSO-d₆): δ=1.20 (d, 6H); 3.51 (s, 2H); 3.72 (s, 3H).

[1678] Optical Rotation: [α]₂₀=+27.9°@589 nm (c=1.00, DMSO).

[1679] C₂₂H₂₅N₃O₄F₂ (MW=433.46); mass spectroscopy (MH⁺) 433.

EXAMPLE 108 Synthesis of N-[N-(Phenylacetyl)-L-phenylglycinyl]-L-alanineEthyl Ester

[1680] Following General Procedure C and using phenylacetic acid(Aldrich) and N-(L-phenylglycinyl)-L-alanie ethyl ester hydrochloride(prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanineethyl ester hydrochloride (Aldrich) using General Procedure C, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=208-210° C.). The reaction wasmonitored by tlc (Rf=0.4 in 5% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 5% MeOHICHCl₃ as the eluent, followedby recrystallization from 1-chlorobutane/acetonitrile.

[1681] NMR data was as follows:

[1682] H-nmr (DMSO-d₆): δ=3.55 (s, 2H); 5.55 (d, 1H).

[1683] Optical Rotation: [α]₂₀=+44.8°@589 nm (c=1.02, DMSO).

[1684] C₂₁H₂₄N₂O₄ (MW=368.43); mass spectroscopy (MH⁺) 369.

EXAMPLE 109 Synthesis ofN-[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycineMethyl Ester

[1685] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine (preparedfrom N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methylester (from Example 94) using General Procedure AF) and L-phenylglycinemethyl ester hydrochloride (Aldrich), the title compound was prepared asa solid (mp=203-207° C.). The reaction was monitored by tlc (Rf=0.3 in10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 10% MeOH/CHCl₃ as the eluent, followed bytrituration using 1-chlorobutane.

[1686] NMR data was as follows:

[1687]¹H-nmr (DMSO-d₆): δ=1.13 (d, 3H); 3.62 (s, 3H).

[1688] Optical Rotation: [°]₂₀=+42.1°@589 nm (c=1.03, DMSO).

[1689] C₂₉H₂₉N₃O₅F₂ (MW=537.56); mass spectroscopy (MH⁺) 537.

EXAMPLE 110 Synthesis ofN-[N-(Cyclohexylacetyl)-L-phenylglycinyl]-L-alanine Ethyl Ester

[1690] Following General Procedure C and using cyclohexylacetic acid(Aldrich) and N-(L-phenylglycinyl)-L-alanine ethyl ester hydrochloride(prepared from N-BOC-L-phenylglycine (Advanced Chemtech) and L-alanineethyl ester hydrochloride (Aldrich) using General Procedure C, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=196-198° C.). The reaction wasmonitored by tlc (Rf=0.3 in 5% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 5% MeOH/CHCl₃ as the eluent, followedby trituration using t-chlorobutane.

[1691] NMR data was as follows:

[1692]¹H-nmr (DMSO-d₆): δ=2.08 (d, 2H); 5.56 (d, 1H).

[1693] Optical Rotation: [α]₂₀=+26.3°@589 nm (c=1.01, DMSO).

[1694] C₂₁H₃₀N₂O₄ (MW=374.48); mass spectroscopy (MH⁺) 375.

Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycineMethyl Ester

[1695] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-phenylglycine methyl ester hydrochloride (Aldrich), the title compoundwas prepared as a solid (mp=198-200° C.). The reaction was monitored bytlc (Rf=0.4 in 4% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 4% MeOH/CHCl₃ as the eluent, followed byrecrystallization from 1- chlorobutane/acetonitrile.

[1696] NMR data was as follows:

[1697]¹H-nmr (DMSO-d₆): δ=1.26 (d, 3H); 3.64 (s, 3H).

[1698] Optical Rotation: (DMSO) [α]₂₀=+69.90°@589 nm (c=1.01, DMSO).

[1699] C₂₀H₂₀N₂O₄F₂ (MW=390.39), mass spectroscopy (MH⁺) 391.

EXAMPLE 112 Synthesis of N-[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-phenylglycine Methyl Ester

[1700] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(L-alaninyl)-L-phenylglycine methyl ester hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and L-phenylglycine methyl ester hydrochloride(Aldrich) using General Procedure C, followed by removal of theBOC-group using General Procedure P), the title compound was prepared asa solid (mp 243-245° C.). The reaction was monitored by tlc (Rf 0.5 in10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 10% MeOH/CHCl₃ as the eluent, followed byrecrystallization from acetonitrile.

[1701] NMR data was as follows:

[1702] H-nmr (DMSO-d,): δ=1.19 (d, 3H); 1.24 (d, 3H).

[1703] Optical Rotation: [α]₂₀=+38.2°@589 nm (c=1.02, DMSO).

[1704] C₂₃H₂₅N₃O₅F₂ (MW=461.46); mass spectroscopy (MH⁺) 461.

EXAMPLE 113 Synthesis ofN-(2-Phenylethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1705] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(2-phenylethyl)-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and phenethylamine (Aldrich) using GeneralProcedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=241-243°C.). The reaction was monitored by tlc (Rf=0.3 in 8% MeOH/CHCl₃) and theproduct was purified by silica gel chromatography using 8% MeOH/CHCl₃ asthe eluent, followed by recrystallization from acetonitrile.

[1706] NMR data was as follows:

[1707]¹H-nmr (DMSOd₆): δ=1.14 (d, 3H); 1.21 (d, 3H).

[1708] Optical Rotation: [α]₂₀=−33.7°@589 nm (c=1.00, DMSO).

[1709] C₂₂H₂₅N₃O₃F₂ (MW=417.45); mass spectroscopy (MH⁺) 417.

EXAMPLE 114 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide

[1710] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and N′-alaninyl)-L-tryptophanamide hydrochloride(prepared from N-BOC-L-alanine (Sigma) and L-tryptophanamidehydrochloride (Sigma) using General Procedure C, followed by removal ofthe BOC-group using General Procedure P), the title compound wasprepared as a solid (mp=199-202° C.). The reaction was monitored by tlc(Rf=0.3 in 15% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 15% MeOH/CHCl₃ as the eluent, followed byrecrystallization from acetonitrile.

[1711] NMR data was as follows:

[1712]¹H-nmr (DMSO-d₆): δ=1.17 (d, 3H); 4.26 (m, 1H); 4.44 (m, 1H).

[1713] Optical Rotation: [α]₂₀=−31.0°@589 nm (c=1.05, DMSO).

[1714] C₂₂H₂₂N₄O₃F₂ (MW=428.44); mass spectroscopy (MH⁺) 428.

EXAMPLE 115 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionate

[1715] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-3-cyclohexylpropionate (Novabiochem), the titlecompound was prepared as a solid (mp=116-119° C.). The reaction wasmonitored by tlc (Rf=0.4 in 4% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 4% MeOH/CHCl₃ as the eluent, followedby recrystallization from 1-chlorobutane/hexanes.

[1716] NMR data was as follows:

[1717]¹H-nmr (DMSO-d₆): δ=1.22 (d, 3H); 3.62 (s, 3H).

[1718] Optical Rotation: [α]₂₀=−21.2°@589 nm (c=1.01, DMSO).

[1719] C₂₁H₂₇N₂O₄F₂ (MW=410.46); mass spectroscopy (MH⁺) 411.

EXAMPLE 116 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(4-nitrophenyl)propionamide

[1720] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(2-methoxyethyl)-(S)-2-amino-3-(4-nitrophenyl)propionamidehydrochloride (prepared from N-BOC-L-4-nitrophenylalanine (AdvancedChemtech) and 2-methoxyethylamine (Aldrich) using General Procedure C,followed by removal of the BOC-group using General Procedure P), thetitle compound was prepared as a solid (mp=263-265° C.). The reactionwas monitored by tlc (Rf=0.5 in 10% MeOH/CHCl₃) and the product waspurified by silica gel chromatography using 10% MeOH/CHCl₃ as theeluent, followed by recrystallization from EtOH/acetonitrile.

[1721] NMR data was as follows:

[1722]¹H-nmr (DMSO-d₆): δ=1.15 (d, 3H); 4.23 (m, 1H); 4.54 (m, 1H).

[1723] Optical Rotation: [α]₂₀=−19.9°@589 nm (c=1.00, DMSO).

[1724] C₂₃H₂₆N₄O₆F₂ (MW=492.48); mass spectroscopy (MH⁺) 493.

EXAMPLE 117 Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-serineEthyl Ester

[1725] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylaceticacid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) usingGeneral Procedure C, followed by hydrolysis using General Procedure AF)and L-serine ethyl ester hydrochloride (Sigma), the title compound wasprepared as a solid (mp=179-181° C.). The reaction was monitored by tlc(Rf=0.2 in 5% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 5% MeOH/CHCl₃ as the eluent.

[1726] NMR data was as follows:

[1727]¹H-nmr (DMSO-d₆): δ=1.20 (m, 6H); 4.30 (m, 1H); 4.41 (m, 1H); 5.04(t, 1H).

[1728] Optical Rotation: [α]₂₀=−19.7°@589 nm (c=1.01, DMSO).

[1729] C₁₆H₂₁N₃O₇ (MW=367.36); mass spectroscopy (MH⁺) 368.

EXAMPLE 118 Synthesis ofN-[(R)-α-Methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1730] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(R)-α-methylbenzyl-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and (R)-α-methylbenzylamine (Aldrich) usingGeneral Procedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=240-242°C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 9%MeOH/CHCl₃ as the eluent, followed by recrystallization fromacetonitrile.

[1731] NMR data was as follows:

[1732]¹H-nmr (DMSO-d₆): δ=1.19 (t, 6H); 1.31 (d, 3H).

[1733] Optical Rotation: [α]₂₀=+1.0°@589 nm (c=1.00, DMSO).

[1734] C₂₂H₂₅N₃O₃F₂ (MW=417.45); mass spectroscopy (MH⁺) 417.

EXAMPLE 119 Synthesis ofN-[(S)-α-Methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1735] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(S)-α-methylbenzyl-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and (R)-α-methylbenzylamine (Aldrich) usingGeneral Procedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=293-295°C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 10%MeOH/CHCl₃ as the eluent, followed by recrystallization fromacetonitrile.

[1736] NMR data was as follows:

[1737]¹H-nmr (DMSO-d₆): δ=1.20 (m, 6H); 1.30 (d, 3H).

[1738] Optical Rotation: [α]₂₀ =−65.9°@589 nm (c=1.05, DMSO).

[1739] C₂₂H₂₅N₃O₃F₂ (MW=417.45); mass spectroscopy (MH⁺) 417.

EXAMPLE 120 Synthesis ofN-(4Fluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1740] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(4-fluorobenzyl)-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and 4-fluorobenzylarnine (Aldrich) using GeneralProcedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=257-259°C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 9%MeOH/CHCl₃ as the eluent, followed by trituration using 1- chlorobutane.

[1741] NMR data was as follows:

[1742]¹H nmr (DMSO-d₆): δ=1.20 (m, 6H); 3.52 (s, 2H).

[1743] Optical Rotation: [α]₂₀=−28.7°@589 nm (c=1.00, DMSO).

[1744] C₂₁H₂₂N₃O₃F₃ (MW=421.42); mass spectroscopy (MH⁺) 421.

EXAMPLE 121 Synthesis ofN-(4-Pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1745] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(4-pyridylmethyl)-L-alaninamide dihydrochloride (prepared fromN-BOC-L-alanine (Sigma) and 4-(aminomethyl)pyridine (Aldrich) usingGeneral Procedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=244-247°C.). The reaction was monitored by tlc (Rf=0.3 in 10% MeOHICHCl₃) andthe product was purified by silica gel chromatography using 10%MeOH/CHCl₃ as the eluent, followed by recrystallization fromacetonitrile.

[1746] NMR data was as follows:

[1747]¹H-nmr (DMSO-d₆): δ=1.21 (d, 3H); 1.26 (d, 3H).

[1748] Optical Rotation: [α]₂₀=−30.3°@589 nm (c=1.00, DMSO).

[1749] C₂₀H₂₂N₄O₃F₂ (MW=404.42); mass spectroscopy (MH⁺) 405.

EXAMPLE 122 Synthesis ofN-(4-Trifluoromethylbenzyl)-N′-[N-(3,5-difuorophenylacetyl)-L-alaninyl-L-alaninamide

[1750] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(4-trifluoromethylbenzyl)-L-alaninamide hydrochloride (prepared fromN-BOC-L-alanine (Sigma) and 4-(trifluoromethyl)benzylamine (Aldrich)using General Procedure C, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid (mp244-247° C.). The reaction was monitored by tlc (Rf=0.4 in 10%MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 8% MeOH/CHCl₃ as the eluent, followed by triturated using1-chlorobutane.

[1751] NMR data was as follows:

[1752]¹H nmr (DMSO-d₆): δ=3.52 (s, 2H); 4.35 (d, 2H).

[1753] Optical Rotation: [α]₂₀=−27.4°@589 nm (c=1.05, DMSO).

[1754] C₂₂H₂₂N₃O₃F₅ (MW=471.43); mass spectroscopy (MH⁺) 471.

EXAMPLE 123 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate

[1755] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and ethyl N-(L-alaninyl)-2-amino-2-phenylpropionatehydrochloride ( prepared from N-BOC-L-alanine (Sigma) andD,L-α-methylphenylglycine ethyl ester (from Example D9 above) usingGeneral Procedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=128-130°C.). The reaction was monitored by tlc (Rf=0.2 in 3 % MeOH/CHCl₃) andthe product was purified by silica gel chromatography using 3 %MeOH/CHCl₃ as the eluent.

[1756] NMR data was as follows:

[1757] H-nmr (DMSO-d₆)(1: 1 mixture of diastereomers): δ=1.72, 1.77(singlets, 3H); 3.52 (s, 2H).

[1758] C₂₂H₂₄N₂O₄F₂ (MW=418.44); mass spectroscopy (MH⁺) 418.

EXAMPLE 124 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylalanine tert-ButylEster

[1759] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and N-(L-alaninyl)-L-phenylalanine tert-butyl esterhydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninetert-butyl ester hydrochloride (Advanced Chemtech) using GeneralProcedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a gel. The reaction wasmonitored by tlc (Rf=0.5 in 4% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 4% MeOH/CHCl₃ as the eluent.

[1760] NMR data was as follows:

[1761]¹H nmr (DMSO-d₆): δ=1.19 (d, 3H); 1.30 (s, 9H).

[1762] C₂₄H₂₈N₂O₄F₂ (MW=446.50); mass spectroscopy (MH⁺) 446.

[1763] Example 125

Synthesis of MethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-methylpropionate

[1764] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-aminoisobutyrate (prepared from 2-aminoisobutyric acid(Aldrich) using General Procedure H), the title compound was prepared asa solid. The reaction was monitored by tlc (Rf=0.25 in CHCl₃/MeOH 95:5).

[1765] NMR data was as follows:

[1766] H-nmr (DMSO-d₆): δ=8.32 (m, 3H), 7.13 (m, 1H), 7.00 (m, 2H), 4.31(m, 1H), 3.53 (m, 5H), 7.08 (m, 1H), 1.36 (s, 3H), 1.34 (s, 3H), 1.19(d, 3H).

[1767] Optical Rotation: [α]₂₃=−25° (c 1, MeOH).

[1768] C₁₆H₂₀N₂O₄F₂ (MW=342.34); mass spectroscopy (MH⁺) 343.

EXAMPLE 126 Synthesis of EthylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-cyclohexylacetate

[1769] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-cyclohexylacetate hydrochloride (prepared fromcyclohexylglycine (Advanced Chemtech) using General Procedure H), thetitle compound was prepared as a solid (mp=146-150° C.). The reactionwas monitored by tlc (Rf=0.3 in 3% MeOH/CHCl₃) and the product waspurified by silica gel chromatography using 3% MeOH/CHCl₃ as the eluent.

[1770] NMR data was as follows:

[1771]¹H-nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=1.60 (m, 6H);3.50 (s, 2H).

[1772] C₂₁H₂₈N₂O₄F₂ (MW=410.46); mass spectroscopy (MH⁺) 410.

EXAMPLE 127 Synthesis ofN-(2-Methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[1773] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(2-methoxyethyl)-L-phenylglycinamide hydrochloride (prepared fromN-BOC-L-phenylglycine (Advanced Chemtech) and 2-methoxyethylamine(Aldrich) using General Procedure C, followed by removal of theBOC-group using General Procedure P), the title compound was prepared asa solid (mp=252-254° C.). The reaction was monitored by tlc (Rf=0.3 in10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 10% MeOH/CHCl₃ as the eluent, followed byrecrystallization from acetonitrile.

[1774] NMR data was as follows:

[1775]¹H nmr (DMSO-d₆): δ=1.22 (d, 3H); 5.43 (d, 1H).

[1776] Optical Rotation: [α]₂₀=+6.17°@589 nm (c=1.04, DMSO).

[1777] C₂₂H₂₅N₃O₄F₂ (MW=433.46); mass spectroscopy (MH⁺) 434.

EXAMPLE 128 Synthesis of N-[N-(Isovaleryl)-2-amino-2-cyclohexylacetyl]-L-alanine Ethyl Ester

[1778] Following General Procedure C and usingN-(isovaleryl)-2-amino2-cyclohexylacetic acid (prepared from isovalericacid (Aldrich) and D,L-α-cyclohexylglycine ethyl ester hydrochloride(prepared from cyclohexylglycine (Advanced Chemtech) and ethanol usingGeneral Procedure H) using General Procedure C, followed by removal ofthe BOC-group using General Procedure P) and L-alanine ethyl esterhydrochloride (Sigma), the title compound was prepared as a solid(mp=220-224° C.). The reaction was monitored by tlc (Rf=0.2 in 5 %MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 5 % MeQH/CHCl₃ as the eluent, followed by recrystallization from1-chlorobutane/acetonitrile.

[1779] NMR data was as follows:

[1780]¹H-nmr (DMSO-d₆): δ=0.85 (d, 6H); 4.04 (m, 2H). C₁₈H₃₂N₂O₄(MW=340.46); mass spectroscopy (MH⁺) 341.

EXAMPLE 129 Synthesis ofN-2-(N,N-Dinethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[1781] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-2-(N,N-dimethylamino)ethyl-L-phenylglycinamide dihydrochloride(prepared from N-BOC-L-phenylglycine (Advanced Chemtech) andN,N-dimethylethylenediamine (Aldrich) using General Procedure C,followed by removal of the BOC-group using General Procedure P), thetitle compound was prepared as a solid (mp=234-236° C.). The reactionwas monitored by tlc (Rf=0.3 in 15% MeOH/CHCl₃) and the product waspurified by silica gel chromatography using 10% MeOH/CHCl₃, followed byslurrying in acetonitrile.

[1782] NMR data was as follows:

[1783]¹H-nmr (DMSO-d₆): δ=1.22 (d, 3H); 5.41 (d, 1H).

[1784] Optical Rotation: [α]₂₀=+5.7°@589 nm (c=1.01, DMSO).

[1785] C₂₃H₂₈N₄O₃F₂ (MW=446.50); mass spectroscopy (MH⁺) 446.

EXAMPLE 130 Synthesis ofN-(2-Pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[1786] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-(2-pyridylmethyl)-L-phenylglycinamide dihydrochloride (prepared fromN-BOC-L-phenylglycine (Advanced Chemtech) and 2-(aminomethyl)pyridine(Aldrich) using General Procedure C, followed by removal of theBOC-group using General Procedure P), the title compound was prepared asa solid (mp=272-275° C.). The reaction was monitored by tlc (Rf=0.4 in10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 10% MeOH/CHCl₃ as the eluent, followed byrecrystallization from acetonitrile.

[1787] NMR data was as follows:

[1788]¹H-nmr (DMSO-d₆): δ=1.24 (d, 3H); 5.50 (d, 1H).

[1789] Optical Rotation: [α]₂₀=+12.4°@589 nm (c=1.02, DMSO).

[1790] C₂₅H₂₄N₄O₃F₂ (MW=466.49); mass spectroscopy (MH⁺) 467.

EXAMPLE 131 Synthesis ofN-[N-(3-Pyridylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1791] Following General Procedure C and using 3-pyridylacetic acidhydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl esterhydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninemethyl ester hydrochloride (Sigma) using General Procedure C, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=150-152° C.). The reaction wasmonitored by tlc (Rf=0.3 in 10% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 10% MeOH/CHCl₃ as the eluent,followed by recrystallization from acetonitrile.

[1792] NMR data was as follows:

[1793]¹H-nmr (DMSO-d,): δ=1.16 (d, 3H); 347 (s, 2H).

[1794] Optical Rotation: [α]₂₀=−19.0°@589 nm (c=1.03, DMSO).

[1795] C₂₀H₂₃N₃O₄ (MW=369.42); mass spectroscopy (MH⁺) 369.

EXAMPLE 132 Synthesis ofN-[N-(2-Pyridylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1796] Following General Procedure C and using 2-pyridylacetic acidhydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl esterhydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninemethyl ester hydrochloride (Sigma) using General Procedure C, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=137-139° C.). The reaction wasmonitored by tlc (Rf=0.4 in 8% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 8% MeOH/CHCl₃ as the eluent, followedby recrystallization from 1-chlorobutane/acetonitrile.

[1797] NMR data was as follows:

[1798]¹H-nmr (DMSO-d₆): δ=1.17 (d, 3H); 3.65 (s, 2H).

[1799] Optical Rotation: [α]₂₀=−17.48°@589 nm (c=1.09, DMSO).

[1800] C₂₀H₂₃N₃O₄ (MW=369.42); mass spectroscopy (MH⁺) 369.

EXAMPLE 133 Synthesis ofN-[N-(4Pyridylacetyl)-L-alaninyl]-L-phenylalanine Methyl Ester

[1801] Following General Procedure C and using 4-pyridylacetic acidhydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl esterhydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalaninemethyl ester hydrochloride (Sigma) using General Procedure C, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=152-154° C.). The reaction wasmonitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃) and the product was purifiedby silica gel chromatography using 10% MeOH/CHCl₃ as the eluent,followed by recrystallization from 1-chlorobutane/acetonitrile.

[1802] NMR data was as follows:

[1803]¹H nmr (DMSO-d₆): δ=1.17 (d, 3H); 3.47 (s, 2H).

[1804] Optical Rotation: [α]₂₀=−17°@589 nm (c=1.00, DMSO).

[1805] C₂₀H₂₃N₃O₄ (MW=369.42); mass spectroscopy (MH⁺) 369.

EXAMPLE 134 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(fluorophenyl)acetate

[1806] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(4-fluorophenyl)acetate hydrochloride (prepared from4-fluorophenylglycine (Fluka) and ethanol using General Procedure H),the title compound was prepared as a solid (mp=169-183° C.). Thereaction was monitored by tlc (Rf=0.3 in 4% MeOH/CHCl₃) and the productwas purified by silica gel chromatography using 4% MeOH/CHCl₃ as theeluent, followed by recrystallization from 1-chlorobutane/acetonitrile.

[1807] NMR data was as follows:

[1808]¹H-nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=3.49, 3.53(singlets, 2H); 5.40 (m, 1H).

[1809] C₂₁H₂₁N₂O₄F₃ (NM=422.4); mass spectroscopy (MH⁺) 422.

EXAMPLE 135 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(2-fluorophenyl)acetate

[1810] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(2-fluorophenyl)acetate hydrochloride (prepared from2-fluorophenylglycine (Fluka) and ethanol using General Procedure H),the title compound was prepared as a solid (mp=153-170° C.). Thereaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl₃) and the productwas purified by silica gel chromatography using 5% MeOH/CHCl₃ as theeluent, followed by recrystallization from 1-chlorobutane/acetonitrile.

[1811] NMR data was as follows:

[1812]¹H nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=3.50, 3.54(singlets, 2H), 5.66 (m, 1H).

[1813] C₂₁H₂₁N₂O₄F₃ (MW=422.40); mass spectroscopy (MH⁺) 422.

EXAMPLE 136 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-alanine Ethyl Ester

[1814] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and N-(L-phenylglycinyl)-L-alanine ethyl esterhydrochloride (prepared from N-BOC-L-phenylglycine (Advanced Chemtech)and L-alanine ethyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid. The reactionwas monitored by tlc (Rf=0.3 in 3% MeOH/CHCl₃) and the product waspurified by silica gel chromatography using 3% MeOH/CHCl₃ as the eluent,followed by recrystallization from 1-chlorobutane/acetonitrile.

[1815] NMR data was as follows:

[1816]¹H nmr (DMSO-d₆): δ=3.50 (s, 2H), 5.53 (d, 1H).

[1817] C₂₁H₂₂N₂O₄F₂ (MW=404.42); mass spectroscopy (MH⁺) 405.

EXAMPLE 137 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionate

[1818] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-3-phthalimidopropionate hydrochloride (from Example D10 above),the title compound was prepared as a solid (mp=197-201° C.). Thereaction was monitored by tlc (Rf=0.5 in 10% MeOH/CHCl₃) and the productwas purified by silica gel chromatography using 5 % MeOH/CHCl₃ as theeluent.

[1819] NMR data was as follows:

[1820]¹H nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=7.88 (m, 4H),8.29 (t, 1H), 8.48, 8.55 (doublets, 1H).

[1821] C₂₄H₂₃N₃O₆F₂ (MW=487.46); mass spectroscopy (MH⁺) 487.

EXAMPLE 138 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine NeopentylEster

[1822] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-phenylglycine neopentyl ester hydrochloride (prepared fromN-BOC-L-phenylglycine (Advanced Chemtech) and 2,2-dimethyl-1-propanol(Aldrich) using General Procedure C (with catalytic DMAP), followed byremoval of the BOC-group using General Procedure P), the title compoundwas prepared as a solid (mp=133-136° C.). The reaction was monitored bytlc (Rf=0.7 in 10% MeOH/CHCl₃) and the product was purified by silicagel chromatography using 4% MeOH/CHCl₃ as the eluent, followed byrecrystallization from 1-chlorobutane/hexanes.

[1823] NMR data was as follows:

[1824]¹H nmr (DMSO-d₆): δ=3.50 (s, 2H), 5.42 (d, 1H).

[1825] Optical Rotation: [α]₂₀=+45.9°@589 nm (c=1.02, DMSO).

[1826] C₂₄H₂₈N₂O₄F₂ (MW=446.50); mass spectroscopy (MH⁺) 446.

EXAMPLE 139 Synthesis ofN-tert-Butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[1827] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),S-(+)-α-methylbenzylamine (Aldrich), benzaldehyde (Aldrich) andtert-butylisocyanide (Aldrich), the title compound was prepared as asolid (mp=233-235° C.). The reaction was monitored by tlc (Rf=0.4 in 10%MeOH/CHCl₃) and the product was purified by silica gel chromatographyusing 8% MeOHICHCl₃ as the eluent, followed by recrystallization from1-chlorobutanelacetonitrile.

[1828] NMR data was as follows:

[1829]¹H nmr (DMSO-d₆)(1:1 mixture of diastereomers): δ=3.52 (s, 2H),5.40 (m, 1H).

[1830] C₂₃H₂₇N₃O₃F₂ (MW=431.49); mass spectroscopy (MH⁺) 432.

EXAMPLE 140 Synthesis ofN-[N-(3,5-Difluorophenylacetyi)-L-alaninyl]-L-phenylglycine tert-ButylEster

[1831] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-phenylglycine tert-butyl ester hydrochloride (Advanced Chemtech), thetitle compound was prepared as a solid (mp=145-147° C.). The reactionwas monitored by tlc (Rf=0.5 in 5% MeOH/CHCl₃) and the product waspurified by silica gel chromatography using 2.5 % MeOH/CHCl₃ as theeluent, followed by recrystallization from 1-chlorobutane/hexanes.

[1832] NMR data was as follows:

[1833]¹H nmr (DMSO-d₆): δ=1.26 (d, 3H); 5.20 (d, 1H).

[1834] Optical Rotation: [α]₂₀=+14.80°@589 nm (c=1.01, MeOH).

[1835] C₂₃H₂₆N₂O₄F₂ (MW=432.47); mass spectroscopy (MH⁺) 433.

EXAMPLE 141 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[1836] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-phenylglycinamide hydrochloride (prepared from N-BOC-L-phenylglycine(Advanced Chemtech) and ammonia using General Procedure C, followed byremoval of the BOC-group using General Procedure P), the title compoundwas prepared as a solid (mp=288-290° C.). The reaction was monitored bytlc (Rf=0.4 in 15% MeOH/CHCl₃) and the product was purified by silicagel chromatography using 15% MeOH/CHCl₃ as the eluent, followed byrecrystallization from EtOH.

[1837] NMR data was as follows:

[1838]¹H-nmr (DMSO-d₆): δ=1.22 (d, 3H), 5.36 (d, 1H).

[1839] Optical Rotation: [α]₂₀=+27.5°@589 nm (c 1.03, DMSO).

[1840] C₁₉H₁₉N₃O₃F₂ (MW=375.38); mass spectroscopy (MH⁺) 376.

EXAMPLE 142 Synthesis of4[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine

[1841] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example DlI above) and4-(L-valinyl)morpholine (prepared from N-BOC-L-valine (Aldrich) andmorpholine (Aldrich) using General Procedure M, followed by removal ofthe BOC-group using General Procedure P), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1CHCl₃/MeOH) and the product was purified by silica gel chromatographyusing 98:2 CHCl₃/MeOH as the eluent.

[1842] NMR data was as follows:

[1843]¹H nmr (CDCl₃): δ=8.12 (d, 2H), 8.08 (dd, 1H), 7.59 (d, 1H, J=7Hz), 7.42 (t, 1H), 7.32 (d, J=8 Hz, 1H), 7.03(d, J=8 Hz, 1H), 4.78(m,1H), 4.68 (m, 1H), 3.61 (m, 10H), 1.90 (m, 1H), 1.96 (d, 3H), 1.31(d, 3H), 0.88 (d, 3H), 0.80 (d, 3H).

[1844] Optical Rotation: [α]₂₃=−5° (c 5, MeOH).

EXAMPLE 143 Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-valineEthyl Ester

[1845] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example Dli above) and L-valineethyl ester hydrochloride (Aldrich), the title compound was prepared asa solid. The reaction was monitored by tlc (Rf=0.2 in 97:3 CHCl₃/MeOH)and the product was purified by silica gel chromatography using 97:3CHCl₃/MeOH as the eluent.

[1846] NMR data was as follows:

[1847]¹H-nmr (CDCl₃): δ=8.13 (m, 2H), 7.62 (d, J=7 Hz, 1H), 7.47 (t,1H), 6.52 (m, 2H), 4.57 (m, 1H), 4.46 (m, 1H), 4.19 (m, 2H), 3.65 (s,2H), 2.13 (m, 1H), 1.38 (d, 3H), 1.22 (t, 3H), 0.82 (d, 3H).

[1848] Optical Rotation: [α]₂₃=24.3°@589 nm (c 1, DMSO).

[1849] C₁₈H₂₅N₃O₆ (MW=379.42); mass spectroscopy (MH⁺) 380.

EXAMPLE 144 Synthesis ofN-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-threonine Methyl Ester

[1850] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example Dl 1 above) andL-threonine methyl ester hydrochloride (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 95:5CHCl₃/ MeOH) and the product was purified by silica gel chromatographyusing 95:5 CHCl₃/MeOH as the eluent.

[1851] NMR data was as follows:

[1852]¹H nmr (CDCl₃): δ=8.08 (d, 1H), 7.96 (d, 1H), 7.59 (d, 1H), 7.45(d, 1H), 7.34 (t, 1H), 7.20 (d, 1H), 4.43 (m, 1H), 4.39 (dd, 1H), 4.13(m, 1H), 3.59 (s, 3H), 3.51 (s, 2H), 1.20 (d, 3H), 1.03 (d, 3H).

[1853] Optical Rotation: [α]₂₃=−20.8° (c 5, MeOH).

[1854] C₁₆H₂₀N₂O₇ (MW=367.3); mass spectroscopy (MH⁺) 368.

EXAMPLE 145 Synthesis of4[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl]morpholine

[1855] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example Dli above) and4-[(S)-2-amino-3-tert-butoxybutyryl]-morpholine (prepared fromN-BOC-O-ter-butyl-L-threonine (Sigma) and morpholine (Aldrich) usingGeneral Procedure M, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid. The reactionwas monitored by tlc (Rf=0.1 in 95:5 CHCl₃/ MeOH) and the product waspurified by silica gel chromatography using 96:4 CHCl₃/ MeOH as theeluent.

[1856] NMR data was as follows:

[1857] H-nmr (CDCl₃): δ=8.12 (m, 2H), 7.66 (d, 1H), 7.47 (t, 1H), 6.88(d, 1H), 6.32 (d, 1H), 4.78 (m, 1H), 4.50 (m, 1H), 3.90-3.40 (m, 11H),1.40 (d, 3H), 1.18 (s, 9H), 1.0 (d, 3H).

[1858] C₂₃H₃₃N₃O₇ (MW=478.5); mass spectroscopy (MH⁺) 479.

EXAMPLE 146 Synthesis of4-[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine

[1859] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example D 1 above) and4-(L-isoleucinyl)morpholine (prepared from N-BOC-L-isoleucine (Aldrich)and morpholine (Aldrich) using General Procedure M, followed by removalof the BOC-group using General Procedure P), the title compound wasprepared as a solid (mp=156-160° C.). The reaction was monitored by tlc(Rf=0.45 in 9:1 CHCl₃/MeOH) and the product was purified by silica gelchromatography using 98:2 CHCl₃/MeOH as the eluent.

[1860] NMR data was as follows:

[1861]¹H nmr (CDCl₃): δ=8.16 (d, 1H), 8.09 (d, 1H), 7.63 (d, 1H), 7.45(t, 1H), 7.30 (d, 1H), 6.89 (d, 1H), 4.78 (m, 1H), 4.62 (m, 1H), 3.6 (m,10H), 1.65 (m, 1H), 1.4 (m, 1H), 1.29 (d, 3H), 1.03 (d, 3H), 0.90-0.76(m, 6H).

[1862] Optical Rotation: [α]₂₃=−55°@589 nm (c 1, MeOH).

EXAMPLE 147 Synthesis ofN-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-isoleucine Methyl Ester

[1863] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example Dl l above) andL-isoleucine methyl ester hydrochloride (Aldrich), the title compoundwas prepared as a solid. The reaction was monitored by tlc (Rf=0.15 in97:3 CHCl₃/MeOH) and the product was purified by silica gelchromatography using 97:3 CHCl₃/MeOH as the eluent.

[1864] NMR data was as follows:

[1865]¹H nmr (CDCl₃): δ=8.12 (m, 2H), 7.66 (d, 1H), 7.49 (t, 1H), 6.50(m, 2H), 4.52 (m, 2H), 3.72 (s, 3H), 3.61 (s, 2H), 1.87 (m, 1H), 1.32(m, 4H), 1.07 (m, 1H), 0.81(d, 6H).

[1866] Optical Rotation: [α]₂₃=−7.3° (c 5, MeOH).

[1867] C₁₈H₂₅N₂O₆ (MW=379); mass spectroscopy (MH⁺) 379.

EXAMPLE 148 Synthesis ofN-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-isoleucine

[1868] Following General Procedure AF and usingN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl ester (fromExample 147 above), the title compound was prepared as a solid.

[1869] NMR data was as follows:

[1870]¹H nmr (DMSO-d₆): δ=8.41 (d, 1H), 8.15 (s, 1H), 8.07 (d, 1H); 7.91(d, 1H), 7.68 (d, 1H), 7.53 (t, 1H), 4.36 (m, 1H), 4.12 (m, 1H), 3.62(s, 2H), 1.71 (m, 1H), 1.31 (m, 1H), 1.18 (d, 3H), 1.07 (m, 1H), 0.79(m, 6H).

[1871] Optical Rotation: [α]₂₃=−42° (c 5, MeOH).

[1872] C₁₇H₂₃N₂O₆ (MW=365.3); mass spectroscopy (MH⁺) 366.

EXAMPLE 149 Synthesis ofN-[N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine EthylEster

[1873] Following General Procedure C and usingN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine (prepared fromN-[N-(3-nitrophenylacetyl)-L-aladnyl]-L-threonine methyl ester (fromExample 144 above) using General Procedure AF) and L-valine ethyl esterhydrochloride (Aldrich), the title compound was prepared as a solid. Thereaction was monitored by tlc (Rf=0.1 in 96:4 CHCl₃/MeOH) and theproduct was purified by silica gel chromatography using 96:4 CHCl₃/MeOHas the eluent.

[1874] NMR data was as follows:

[1875] H-nmr (CDCl₃): δ=8.12 (m, 1H), 7.60 (d, 1H), 7.48 (t, 1H), 7.05(d, 1H), 6.98 (d, 1H), 6.48 (d, 1H), 4.60 (m, 1H), 4.47 (m, 3H), 4.22(m, 2H) 3.65 (s, 2H), 2.19 (m, 1H), 1.38 (d, 3H), 1.28 (t, 3H), 1.09 (d,3H), 0.87 (m, 6H).

[1876] Optical Rotation: [α]₂₃=−85° (c 5, MeOH).

EXAMPLE 150 Synthesis of MethylN-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate

[1877] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example DlI above) and methyl(S)-2-aminopentanoate hydrochloride (prepared from (S)-2-aminopentanoicacid (Novabiochem) using General Procedure H), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.4 in 9:1CHCl₃/MeOH).

[1878] NMR data was as follows:

[1879]¹H nmr (DMSO-d₆): δ=8.39 (m, 1H), 8.28 (m, 1H), 8.19 (m, 1H), 8.11(m, 1H), 7.73 (d, 1H), 7.61 (d, 1H), 4.36 (m, 1H), 4.22 (m, 1H), 3.64(m, 5H), 1.62 (m, 2H), 1.26 (m, 2H), 1.22 (d, 3H), 0.86 (m, 3H).

[1880] Optical Rotation: [α]₂₃=−29° (c 1, MeOH).

[1881] C₁₇H₂₃N₃O₆ (MW=365); mass spectroscopy (MH⁺) 366.

EXAMPLE 151 Synthesis ofN-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-leucine Methyl Ester

[1882] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example Dll above) and L-leucinemethyl ester hydrochloride (Aldrich), the title compound was prepared asa solid. The reaction was monitored by tlc (Rf=0.75 in 9:1 CHCl₃/MeOH)and the product was purified by silica gel chromatography using 97:3CHCl₃/MeOH as the eluent.

[1883] NMR data was as follows:

[1884]¹H nmr (CDCl₃): δ=8.12 (m, 2H), 8.04 (m, 1H), 7.58 (m, 1H), 7.48-7.30 (m, 2H), 7.11 (d, 1H), 4.63 (m, 1H), 4.48 (m, 1H), 3.68 (s, 2H),3.64 (s, 3H), 1.63 (m, 1H), 1.31 (m, 2H), 0.85 (d, 3H), 0.82 (m, 3H).

[1885] Optical Rotation: [α]₂₃=−320 (c 1, MeOH).

[1886] C₁₈H₂₅N₃O₆ (MW=379); mass spectroscopy (MH⁺) 380.

EXAMPLE 152 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-leucine Methyl Ester

[1887] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-leucine methyl ester hydrochloride (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1CHCl₃/MeOH).

[1888] NMR data was as follows: ¹H-nmr (CDCl₃): δ=6.78 (m, 2H), 6.69 (m,1H), 4.52 (m, 2H), 3.73 (m, 1H), 3.52 (d, 2H), 1.63 (m, 2H), 1.36 (m,3H), 0.88 (m, 3H).

[1889] Optical Rotation: [α]₂₃=−34° (c 1, MeOH).

[1890] C₁₈H₂₄N₂O₄F₂ (MW=370); mass spectroscopy (MH⁺) 370.

EXAMPLE 153 Synthesis ofN-2-Methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1891] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and 2-methoxyethylamnine (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.35 in 9:1CHCl₃/ MeOH).

[1892]

[1893] NMR data was as follows:

[1894]¹H nmr (DMSO-d₆): δ=8.32 (m, 1H), 7.98 (d, 1H), 7.82 (m, 1H), 7.07(m, 1H), 6.97 (m, 2H), 4.25 (m, 2H), 3.52 (s, 2H), 3.32 (m, 31), 3.20(m, 4H), 1.19 (m, 6H).

[1895] Optical Rotation: [α]₂₃=−50° (c 1, MeOH).

[1896] C₁₇H₂₃N₃O₄F₂ (MW=371); mass spectroscopy (MH⁺) 372.

EXAMPLE 154 Synthesis ofN-2-(N,N-Dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninaminde

[1897] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and N,N-dimethylethylenediamine (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.05 in 9:1CHCl₃/MeOH).

[1898] NMR data was as follows:

[1899]¹H nmr (DMSO-d₆): δ=8.38 (m, 1H), 8.02 (m, 1H), 7.66 (m, 1H), 7.09(m, 1H), 6.97 (m, 2H), 4.22 (m, 2H), 3.53 (s, 2H), 3.08 (m, 2H), 2.22(m, 2H), 2. 11 (m, 6H), 1. 21 (d, 6H).

[1900] Optical Rotation: [α]₂₃=−55° (c 1, MeOH).

[1901] C₁₈H₂₆N₄O₃F₂ (MW=384); mass spectroscopy (MH⁺) 384.

EXAMPLE 155 Synthesis ofN-Cyclohexyl-N′[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1902] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and cyclohexylarnine (Aldrich), the title compound was preparedas a solid (mp=239-244° C.). The reaction was monitored by tlc (Rf=0.25in 9:1 CHCl₃/MeOH).

[1903] NMR data was as follows:

[1904]¹H-nmr (DMSO-d₆): δ=8.39 (m, 1H), 7.94 (m, 1H), 7.56 (m, 1H), 7.08(m, 1H), 6.97 (m, 2H), 4.20 (m, 2H), 3.32 (s, 2H), 3.27 (m, 1H), 1.64(m, 4H), 1.54 (m, 2H), 1.20 (m, 10H).

[1905] Optical Rotation: [α]₂₃=58° (c 1, MeOH).

[1906] C₂₀H₂₇N₃O₃F₂ (MW 395); mass spectroscopy (MH⁺) 395.

EXAMPLE 156 Synthesis ofN-Neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1907] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and neopentylamine (Aldrich), the title compound was prepared asa solid. The reaction was monitored by tlc (Rf=0.25 in 9:1 CHCl₃/ MeOH).

[1908] NMR data was as follows:

[1909]¹H nmr (DMSO-d₆): δ=8.37 (d, 1H), 8.01 (m, 1H), 7.67 (m, 1H), 7.11(m, 1H), 6.98 (m, 2H), 4.28 (m, 2H), 3.51 (s, 2H), 2.88 (m, 2H), 1.23(d, 3H), 0.80 (m, 9H).

[1910] Optical Rotation: [α]₂₃=−54° (c 1, MeOH).

[1911] C₁₉H₂₇N₃O₃F₂ (MW=383); mass spectroscopy (MH⁺) 383.

EXAMPLE 157 Synthesis ofN-Tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1912] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and tetrahydrofurfurylamine (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.20 in 9:1CHCl₃/MeOH).

[1913] NMR data was as follows:

[1914]¹H-nmr (DMSO-d₆): δ=8.36 (d, 1H), 8.01 (m, 1H), 7.81 (m, 1H), 7.11(m, 1H), 6.99 (m, 2H), 4.25 (m, 2H), 3.77 (m, 2H), 3.58 (m, 1H), 3.51(s, 2H), 3.21 (m, 1H), 1.78 (m, 4H), 1.46 (m, 1H), 1.19 (m, 6H).

[1915] Optical Rotation: [α]₂₃=−70° (c 1, MeOH). Cl₉H₂₅N₃O₄F₂ (MW 397);mass spectroscopy (MH⁺) 398.

EXAMPLE 158 Synthesis ofN-2-Pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1916] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and 2-(aminomethyl)pyridine (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.1 in 9:1CHCl₃/MeOH).

[1917] NMR data was as follows:

[1918]¹H nmr (DMSO-d₆): δ=8.49 (m, 1H), 8.41 (m, 2H), 8.14 (d, 1H), 7.74(m, 1H), 7.28 (m, 2H), 7.09 (m, 1H), 6.98 (m, 2H), 4.33 (m, 4H), 3.52(s, 2H), 1.24 (m, 6H).

[1919] Optical Rotation: [α]₂₃=−68° (c 5, MeOH).

[1920] C₂₀H₂₂N₄O₃F₂ (MW=404); mass spectroscopy (MH⁺) 405.

EXAMPLE 159 Synthesis of 3[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine

[1921] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and thiazolidine (Aldrich), the title compound was prepared as asolid. The reaction was monitored by tlc (Rf=0.25 in 9:1 CHCl₃/MeOH).

[1922] NMR data was as follows:

[1923]¹H-nmr (DMSO-d₆): δ=8.34 (m, 2H), 8.22 (m, 1H), 7.09 (m, 1H), 6.98(m, 2H), 4.68-4.23 (m, 4H), 3.81-3.6 (m, 2H), 3.52 (s, 2H), 3.01 (m,2H), 1.19 (m, 6H).

[1924] Optical Rotation: [α]₂₃=−67° (c 1, MeOH).

[1925] C₁₇H₂₁N₃O₃F₂ (MW 385); mass spectroscopy (MH⁺) 385.

EXAMPLE 160 Synthesis of MethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate

[1926] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-aminobutanoate hydrochloride (prepared from(S)-(+)-2-aminobutyric acid (Aldrich) using General Procedure H), thetitle compound was prepared as a solid (mp=103-106° C.).

[1927] NMR data was as follows:

[1928]¹H-nmr (CDCl₃): δ=6.83 (m, 2H), 6.72 (m, 1H), 6.49 (d, 1H), 4.55(m, 1H), 4.48 (m, 1H), 3.72 (s, 3H), 3.49 (s, 2H), 1.85 (m, 1H), 1.69(m, 1H), 1.39 (d, 3H), 0.86 (t, 3H).

[1929] Optical Rotation: [α]₂₃=−70° (c 1, MeOH).

[1930] C₁₆H₂₀N₂O₄F₂ (MW=342.35); mass spectroscopy (MH⁺) 342.

EXAMPLE 161 Synthesis of MethylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate

[1931] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-aminopentanoate hydrochloride (prepared from(S)-2-aminopentanoic acid (Novabiochem) using General Procedure H), thetitle compound was prepared as a solid (mp=154- 155C.).

[1932] NMR data was as follows:

[1933] H-nmr (CDCl₃): δ=6.80 (m, 2H), 6.69 (m, 1H), 6.45 (d, 1H), 6.28(d, 1H), 4.52 (m, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 1.77 (m, 1H), 1.58(m, 1H), 1.35 (d, 3H), 1.27 (m, 2H), 0.87 (t, 3H).

[1934] Optical Rotation: [α]₂₃=−69° (c 1, MeOH).

EXAMPLE 162 Synthesis of MethylN-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate

[1935] Following General Procedure C and usingN-(3-nitrophenylacetyl)-L-alanine (from Example DI 1 above) and methyl(S)-2-aminobutanoate hydrochloride (prepared from (S)-(+)-2-aminobutyricacid (Aldrich) using General Procedure H), the title compound wasprepared as a solid (mp=154-157° C.).

[1936] NMR data was as follows:

[1937]¹H nmr (CDCl₃): δ=8.13 (m, 1H), 8.04 (m, 1H), 7.57 (m, 1H), 7.38(m, 1H), 4.72 (m, 1H), 4.39 (m, 1H), 3.69 (s, 3H), 3.41 (s, 2H), 1.73(m, 1H), 1.61 (m, 1H), 1.34 (d, 3H), 0.79 (t, 3H).

[1938] Optical Rotation: [α]₂₃=−75° (c 1, MeOH).

EXAMPLE 163 Synthesis ofN-(R)-sec-Butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1939] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and (R)-(-)-sec-butylamine (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.15 in 95:5CHCl₃/MeOH) and the product was purified by silica gel chromatographyusing 95:5 CHCl₃ MeOH as the eluent.

[1940] NMR data was as follows:

[1941]¹H nmr (DMSOd₆): δ=8.39 (m, 1H), 7.95 (m, 1H), 7.49 (m, 1H), 7.09(m, 1H), 7.01 (m, 2H), 4.20 (m, 4H), 3.61 (m, 1H), 3.52 (s, 2H), 1.34(m, 2H), 1.21 (m, 6H), 0.97 (d, 3H), 0.79 (m, 3H).

[1942] Optical Rotation: [α]₂₃=−50° (c 1, MeOH).

[1943] C₁₈H₂₅N₃O₃F₂ (MW=369.41); mass spectroscopy (MH⁺) 370.

EXAMPLE 164 Synthesis of1-[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine

[1944] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and pyrrolidine (Aldrich), the title compound was prepared as asolid. The reaction was monitored by tlc (Rf=0.15 in 95:5 CHCl₃/ MeOH)and the product was purified by silica gel chromatography usingCHCl₃/MeOH as the eluent.

[1945] NMR data was as follows:

[1946]¹H nmr (DMSO-d₆): δ=8.31 (m, 1H), 8.08 (m, 1H), 7.09 (m, 1H), 6.99(m, 2H), 4.48 (m, 1H), 4.29 (m, 1H), 3.51 (s, 2H), 3.44-3.22 (m, 4H),1.80 (m, 4H), 1.27 (m, 6H).

[1947] C₁₈H₂₃N₃O₃F₂ (MW=367.40); mass spectroscopy (MH⁺) 367.

EXAMPLE 165 Synthesis of N-(S)-sec-Butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1948] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and (S)-(+)-sec-butylamine (Aldrich), the title compound wasprepared as a solid, The reaction was monitored by tlc (Rf=0.25 in 9:1CHCl₃/MeOH) and the product was purified by silica gel chromatographyusing CHCl₃/MeOH as the eluent.

[1949] NMR data was as follows:

[1950]¹H nmr (DMSO-d₆): δ=8.38 (m, 1H), 7.92 (m, 1H), 7.30 (m, 1H), 7.18(m, 1H), 6.99 (m, 2H), 4.20 (m, 4H), 3.62 (m, 1H), 3.52 (s, 2H), 1.34(m, 2H), 1.20 (m, 6H), 1.01 (m, 3H), 0.81 (t, 3H).

[1951] Optical Rotation: [α]₂₃=−52° (c 1MeOH).

[1952] C₁₉H₂₅N₃O₃F₂ (MW=369.41); mass spectroscopy (MH⁺) 370.

EXAMPLE 166 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-valine Methyl Ester

[1953] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-valine methyl ester hydrochloride (Aldrich), the title compound wasprepared as a solid.

[1954] NMR data was as follows:

[1955]¹H-nmr (CDCl₃): δ=6.81 (m, 2H), 6.73 (m, 1H), 6.48 (d, 1H), 6.22(d, 1H), 4.48 (m, 2H), 3.70 (s, 3H), 3.51 (s, 2H), 2.16 (m, 1H), 1.37(m, 1H), 0.87 (t, 3H).

[1956] Optical Rotation: [α]₂₃=−65° (c 1, MeOH).

[1957] C₁₇H₂₂N₂O₄F₂ (MW=356.37); mass spectroscopy (MH⁺) 360.

EXAMPLE 167 Synthesis ofN-2-Fluoroethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide

[1958] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine (from Example D7above) and 2-fluoroethylamine hydrochloride (Aldrich), the titlecompound was prepared as a solid (mp=230-235° C.).

[1959] NMR data was as follows:

[1960]¹H nmr (DMSOd₆): δ=8.38 (d, 1H), 8.04 (m, 2H), 7.07 (m, 1H), 6.99(m, 2H), 4.39 (m, 2H), 4.24 (m, 1H), 3.53 (s, 2H), 3.35 (m, 2H), 1.20(m, 6H).

[1961] Optical Rotation: [α]₂₃=−33° (c 1, MeOH).

[1962] C₁₆H₂₀N₃O₃F₃ (MW=359.37); mass spectroscopy (MH⁺) 359.

EXAMPLE 168 Synthesis ofN-[(S)-6Methyl-3-oxohept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[1963] Following General Procedure M and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(S)-6-methyl-3-oxohept-2-ylamine hydrochloride (prepared by treatingN-BOC-L-alanine N-methoxy-N-methyl amide (Weinreb et al., TetrahedronLett., 22, 3815 (1981)) with isopropyl magnesium bromide (Aldrich),followed by removal of the BOC group using General Procedure P), thetitle compound was prepared as a solid. The product was purified bysilica gel chromatography using CHCl₃/MeOH as the eluent.

[1964] NMR data was as follows:

[1965]¹H nmr (CDCl₃): δ=6.84 (m, 2H), 6.69 (m, 1H), 6.31 (m, 1H), 4.50(m, 2H), 3.51 (s, 2H), 2.48 (m, 2H), 1.47 (m, 2H), 1.32 (m, 7H), 0.90(d, 6H).

[1966] Optical Rotation: [α]₂₃=−42° (c 1, MeOH).

[1967] C₁₉H₂₆N₂O₃F₂ (MW=368); mass spectroscopy (MH⁺) 368.

EXAMPLE 169 Synthesis ofN-4Nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramide

[1968] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyric acid(prepared from methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate (fromExample 160 above) using General Procedure AF) and 4-nitrobenzylamine(Aldrich), the title compound was prepared as a solid. The reaction wasmonitored by tlc (Rf=0.3 in 95:5 CHCl₃/MeOH) and the product waspurified by silica gel chromatography using 97:3 CHCl₃/ MeOH as theeluent.

[1969] NMR data was as follows:

[1970]¹H-nmr (DMSO-d₆): δ=8.57 (t, 1H), 8.40 (d, 1H), 8.21 (d, 2H), 8.02(d, 1H), 7.50 (d, 2H), 7.08 (m, 1H), 6.98 (m, 2H), 4.42 (d, 2H), 4.37(m, 1H), 4.17 (m, 1H), 3.53 (s, 2H), 1.64 (m, 2H), 1.21 (m, 3H), 0.83(t, 3H).

[1971] Optical Rotation: [α]₂₃=−42° (c 1, MeOH).

[1972] C₂₂H₂₄N₄O₅F₂ (MW=462.45); mass spectroscopy (MH⁺) 462.

EXAMPLE 170 Synthesis ofN-4-Nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamide

[1973] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoic acid(prepared from methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate (fromExample 161 above) using General Procedure AF) and 4-nitrobenzylamine(Aldrich), the title compound was prepared as a solid. The reaction wasmonitored by tlc (Rf=0.3 in 95:5 CHCl₃/MeOH) and the product waspurified by recrystallization from acetonitrile.

[1974] NMR data was as follows:

[1975]¹H nmr (DMSO-d₆): δ=8.57 (m, 1H), 8.41 (d, 1H), 8.22 (d, 2H), 8.06(d, 1H), 7.51 (d, 2H), 7.12 (m, 1H), 7.00 (m, 2H), 4.43 (d, 2H), 4.30(m, 2H), 3.56 (s, 2H), 1.65 (m, 2H), 1.29 (m, 5H), 0.91 (t, 3H).

[1976] Optical Rotation: [α]₂₃=+970 (c 1, MeOH).

[1977] C₂₃H₂₆N₄O₅F₂ (MW=476.4); mass spectroscopy (MH⁺) 476.

EXAMPLE 171 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetate

[1978] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride (from EXAMPLE D12above), the title compound was prepared as a solid. The reaction wasmonitored by tlc (Rf=0.2 in 95:5 CHCl₃/MeOH) and the product waspurified by silica gel chromatography using 95:5 CHCl₃/MeOH as theeluent.

[1979] NMR data was as follows:

[1980]¹H nmr (CDCl₃):=7.36 (m, 1H), 7.18 (m, 1H), 7.13 (m, 1H), 7.06 (m,1H), 6.87 (m, 2H), 6.74 (m, 1H), 6.09 (m, 1H), 5.49 (d, 1H), 4.59 (m,1H), 3.74 (s, 3H), 3.57 (s, 2H), 1.35 (d, 3H), 0.97 (d, 3H).

[1981] C₂₀H₁₉N₂O₄F₃ (MW=408.38); mass spectroscopy (MH⁺) 408.

EXAMPLE 172 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamide

[1982] Following General Procedure L and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate(from Example 178 below), the title compound was prepared as a solid(mp=decomposition at 190° C.). The product was purified by preparativeLC 2000 chromatography using 8:2 EtOAc/hexanes as the eluent.

[1983] NMR data was as follows:

[1984]¹H-nmr (CDCl₃/DMSO-d₆): δ=8.9-6.14 (Ar +NH's 10 H), 5.43-5.39 (m,1H), 4.16-4.10 (m, J=7 Hz, 1H), 3.19 (s, 2H), 1.15 (d, J=7.05 Hz, 3H).

[1985] C₁₇H₁₇F₂N₃O₃S (MW 381.4); mass spectroscopy (MH⁺) 381.

EXAMPLE 173 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetate

[1986] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(5-chlorobenzothiophen-2-yl)acetate (prepared from5-chlorobenzothiophene-2-acetic acid [CAS No. 23799-65-7] using GeneralProcedure G, followed by amination using a procedure essentially thesame as that described in Example D4 above), the title compound wasprepared as a solid (mp=189-190° C.). The product was purified bytitration using Et20/hexanes.

[1987] NMR data was as follows:

[1988]¹H-nmr (CDCl₃): δ=7.7-7.63 (m, 2H), 7.33-7.17 (m, 2H), 6.89-6.63(m, 3H), 6.16-6.03 (m, 1H), 5.85 (dd, 1H), 4.7-4.53 (m, 1H), 3.83 (s,1.5H), 3.8 (s, 1.5H), 3.59 (s, 1H), 3.5 (s, 1H), 1.4 (dt, 3H).

[1989] C₂₂H₁₉CIF₂N₂O₄S (MW=481); mass spectroscopy (MH⁺) 480.

EXAMPLE 174 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetate

[1990] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(benzothiophen-2-yl)acetate [CAS No. 98800-64-7], the titlecompound was prepared as a solid (mp=189-190° C.). The product waspurified by preparative LC 2000 chromatography using 2:8 EtOAc/hexanesas the eluent.

[1991] NMR data was as follows:

[1992]¹H nmr (CDCl₃): δ=7.8-7.75 (m, 2H), 7.34-7.27 (m, 2H), 7.25-7.09(m, 3H), 6.81-6.76 (m, 1H), 6.76-6.63 (m, 1H), 6.23 (dd, J=7 Hz, 1H),5.84(d, J=7.07 Hz, 1H), 4.61-4.59 (m, 1H), 4.33-4.2 (m, 2H), 3.54 (s,1H), 3.50 (s, 1H), 1.70 (d, J=11.9 Hz, 1.5H), 1.38 (d, J=11.9 Hz, 1.5H), 1.36-1.23 (dt, 3H).

[1993] C₂₃H₂₂N₂O₄SF₂ (MW=460.49); mass spectroscopy (MH⁺) 460.

EXAMPLE 175 Synthesis of MethylN-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-3-yl)acetate

[1994] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(benzothiophen-3-yl)acetate (prepared from2-amino-2-(benzothiophen-3-yl)acetic acid [CAS 95834-94-9] using GeneralProcedure H), the title compound was prepared as a solid (mp 185-186°C.).

[1995] NMR data was as follows:

[1996] H-nmr (CDCl₃): δ=7.86 (m, 2H), 7.4-7.3 (m, 3H), 7.4-7.2 (m, 2H),6.9-6.6 (m, 3H), 6.3-6.13 (m, 1H), 5.95-5.85 (m, 1H), 4.55-4.5 (m, 1H),3.75 (s, 1.5H), 3.65 (s, 1.5H), 3.55 (s, 1H), 3.35 (s, 1H), 1.4 (d,1.5H), 1.3 (d, 1.5H).

[1997] C₂₂H₂₀N₂O₄F₂S (MW=446); mass spectroscopy (MH⁺) 446.

EXAMPLE 176 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate

[1998] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(2-thienyl)acetate (prepared from L-u-2-thienylglycine(Sigma) using General Procedure G), the title compound was prepared as asolid (mp=161-162° C.). The product was purified by preparative LC 2000chromatography using 1:4 EtOAc/hexanes.

[1999] NMR data was as follows:

[2000]¹H-nmr (CDCl₃): δ=7.3-6.65 (Ar, 7H), 6.25 (bt, 1H), 5.8 (dd, 1H),4.68-4.5 (m, 1H), 3.85 (s, 1H), 3.75 (s, 1H), 3.52 (s, 1H), 3.5 (s, 1H),1.35 (overlaying d, 3H).

[2001] C₁₈H₁₈N₂O₄F₂S (MW=396); mass spectroscopy (MH⁺) 396.1.

EXAMPLE 177 Synthesis of EthylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2amino-2-(benzothiophen-5yl)acetate

[2002] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl2-amino-2-(benzothiophen-5-yl)acetate (prepared as described in S.Kukolja et al., J. Med. Chem., 1985, 28, 1896-1903), the title compoundwas prepared as a solid (mp=126.5-127.5° C.). The product was purifiedby preparative LC 2000 chromatography using 1:1 hexanes/EtOAc as theeluent.

[2003] NMR data was as follows:

[2004]¹H nmr (CDCl₃):=8.1 (s, 1H), 8.05 (s, 1H), 7.6-7.5 (m, 2H),7.4-7.25 (m, 3H), 7.15 (bd, J=12 Hz, 5H), 7.05 (bd, J=12 Hz, 5H),6.89-6.675 (m, 2H), 6.225 (bd, J=12 Hz, 5H), 6.075 (bd, J=12 Hz, 5H),4.55 (q, J=7.5 Hz, 1H), 4.2 (dq, 2H), 3.575 (s, 1H), 3.242 (s, 1H), 1.4(d, J=7.05 Hz, 1.5H), 1.15 (d, J=7.05 Hz, 1.5H).

[2005] C₂₃H₂₂N₂O₄F₂S (MW=460); mass spectroscopy (MH⁺) 460.1.

EXAMPLE 178 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(2-thienyl)acetate

[2006] Following General Procedure G and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticacid (from Example 180 below), the title compound was prepared as asolid (mp=180-181° C.). The product was purified by preparative LC 2000chromatography using 6:4 EtOAc/hexanes as the eluent.

[2007] NMR data was as follows:

[2008]¹H nmr (CDCl₃): δ=7.3-6.6 (Ar +NH, 7H), 6.37 (bd, J=7 Hz, 1H),5.77 (d, J=7 Hz, 1H), 4.6-4.56 (m, J=7 Hz, 1H), 3.7 (s, 3H), 3.4 (s,2H), 1.38 (d, J=7 Hz, 3H).

[2009] C₁₈H₁₈N₂O₄SF₂ (MW=396); mass spectroscopy (MH⁺) 396.1.

EXAMPLE 179 Synthesis of tert-ButylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2(2-thienyl)acetate

[2010] Following General Procedure J and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amini2-(2-thienyl)aceticacid (from Example 180 below), the title compound was prepared as asolid (mp=117-118° C.). The product was purified by tituraration usingether/hexanes.

[2011] NMR data was as follows:

[2012]¹H-nmr (CDCl₃): δ=7.24 (d, J=6.5 Hz, 1H), 7.05-6.63 (m, 6H), 6.19(bd, J=7.2 Hz, 1H), 5.66 (d, J=7.5 Hz, 1H), 4.6-4.5 (m, 1H), 3.5 (s,2H), 1.44 (s, 9H), 1.38 (d, J=7.1 Hz, 3H).

[2013] C₂₁H₂₄N₂O₄SF₂ (MW 438.5); mass spectroscopy (MH⁺) 438.

EXAMPLE 180 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticAcid

[2014] Following General Procedure M and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-ce-2-thienylglycine (Sigma), the title compound was prepared as asolid. The product was purified by tituration using EtOAc/hexanes.

[2015] NMR data was as follows:

[2016]¹H nmr (DMSO-d₆): δ=8.73 (d, J=7 Hz, 1H), 8.38 (d, J=7 Hz, 1H),7.56-7.4 (m, 1H), 7.2-6.9 (m, 4H), 5.54 (d, J=8 Hz, 1H), 4.5-4.3 (m,1H), 3.33 (s, 2H), 1.23 (d, J=7 Hz, 3H).

[2017] C₁₇H₁₆N₂O₄SF₂ (MW=382); mass spectroscopy (MH⁺) 382.

EXAMPLE 181 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(1H-tetrazol-5-yl)acetate

[2018] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(1H-tetrao1-5-yl)acetate (prepared from ethyl1H-tetrazole-5-acetate [CAS 173367-99-2] using procedures essentiallythe same as those described in S. Kukolja, J. Med. Chem., 1985, 28,1886-1896), the title compound was prepared as a solid. The reaction wasproduct was purified by tituration using EtOAc/hexanes.

[2019] NMR data was as follows:

[2020]¹H nmr (DMSO-d₆): δ=9.13 (d, J=7.6 Hz, 1H), 8.39 (t, J=7 Hz, 1H),7.1-6.95 (m, 3H), 5.9 (dd, 1H), 4.4-4.3 (m, 1H), 4.14 (q, J=7 Hz, 2H),3.5 (s, 3H), 1.27-1.11 (m, 6H).

[2021] C₁₆H₁₈N₆O₄F₂ (MW 396.3); mass spectroscopy (MH⁺) 396.3.

EXAMPLE 182 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate

[2022] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (S)-2-amino-2-(6-methoxy-2-naphthyl)acetate (from Example D3above), the title compound was prepared as a solid (mp=177-178° C.). Theproduct was purified by tituration using hexanes/EtOAc.

[2023] NMR data was as follows:

[2024]¹H-nmr (DMSO-d₆): δ=8.84 (d, J=9 Hz, 1H), 8.4 (d, J=9 Hz, 1H),7.90-7.76 (m, 2H), 7.247-6.90 (m, 5H), 5.5 (J=7 Hz, 1H), 4.243 (d, J=3.5Hz, 1H), 3.86 (s, 3H), 3.6 (s, 3H), 3.29 (s, 2H), 1.26 (d, J=7.5 Hz,3H).

[2025] C₂₅H₂₄N₂O₅F₂ (MW=470.48); mass spectroscopy (MH⁺) 470.

EXAMPLE 183 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetate

[2026] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(3-trifluoromethylphenyl)acetate (prepared from2-(hydroxyimino)-2-(3-trifluoromethylphenyl)acetic acid [CAS179811-81-5] using General Procedures G and R above), the title compoundwas prepared as a solid (mp=133-134° C.). The product was purified bytituration from EtOAc/hexanes.

[2027] NMR data was as follows:

[2028]¹H nmr (CDCl₃): δ=7.57-7.37 (m, 4H), 6.8-6.6 (m, 3H), 6.05 (BA,1H), 5.5 (A, J=7.5Hz, 1H), 3.7 (s, 1.5H), 3.675 (s, 1.5H), 3.5 (s, 1H),3.45 (s, 1H), 1.33 (d, J=7.5 Hz, 1.5H), 1.-275 (d, J=7.5 Hz, 1.5H).

[2029] C₂₁H₁₉N₂O₄F₅ (MW=458.39); mass spectroscopy (MH⁺) 459.

EXAMPLE 184 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate

[2030] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate (preparedfrom N-Boc-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetic acid[CAS 95361-97-0] using General Procedures G above and the Boc removalprocedure described in Example D3 above), the title compound wasprepared as a solid. The product was purified by tituration usingEt₂O/hexanes.

[2031] NMR data was as follows:

[2032]¹H nmr (CDCl₃): δ=7.05 (d, J=5 Hz, 1H), 7.02 (d, J=5 Hz, 1H),6.82-6.66 (m, 3H), 6.31 (bd, J=8 Hz, 1H), 5.66 (dd, J=7.2 Hz, 1H),4.63-4.55 (m, 1H), 3.76 (s, 1.5H), 3.75 (s, 1.5H), 3.52 (s, 1H), 3.50(s, 1H), 2.67-2.65 (m, 2H), 2.54-2.52 (m, 2H), 1.77-1.7 (m, 4H), 1.36(dd, J=7 Hz, 3H).

[2033] C₂₂H₂₄N₂O₄F₂S (MW=450); mass spectroscopy (MH⁺) 450.

EXAMPLE 185 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2(thieno[2,3-b]thiophen-2ylacetate

[2034] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (from Example D4above), the title compound was prepared as a solid. The product waspurified by titruation from Et₂O/ hexanes.

[2035] NMR data was as follows:

[2036]¹H-nmr (CDCl₃): δ=7.35 (d, J=7.5 Hz, 1H), 7.2-7.0 (m, 3H),6.9-6.69 (m, 3H), 6.13-6.0 (m, 1H), 5.8 (dd, 1H), 4.63-4.5 (m, 1H), 3.8(s, 3H), 3.58 (s, 1H), 3.469 (1H), 1.4 (dd, 3H).

[2037] C₂₀H₁₈N₂O₄F₂S₂ (MW=452); mass spectroscopy (MH⁺) 452.

EXAMPLE 186 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazolfyl)acetate

[2038] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(2-methylthiazol-4-yl)acetate (prepared fromN-Boc-2-amino-2-(2-methylthiazol-4-yl)acetic acid [CAS 105381-90-6]using General Procedure H above), the title compound was prepared as asolid. The product was purified by tituration using Et₂O/ hexanes.

[2039] NMR data was as follows:

[2040]¹H nmr (CDCl₃): δ=7.2-6.66 (pr +NH, 5H), 5.69-5.6 (m, 1H),4.8-4.69 (m, 1H), 3.76 (s, 3H), 3.56 (s, 1H), 3.5 (s, 1H), 2.69 (s, 3H),1.4 (d, J=14 Hz, 1.5H), 1.35 (s, J=14 Hz, 1.5H).

[2041] C₁₈H₁₉N₃O₄F₂S (MW=411); mass spectroscopy (MH⁺) 411.

EXAMPLE 187 Synthesis of Methyl(3S,4S)-N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-4amino-3-hydroxy-5-phenylpentanoate

[2042] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoate (Novabiochem), thetitle compound was prepared as a solid. The reaction was monitored bytlc (Rf=0.2 in 95:5 CHCl₃/MeOH) and the product was purified by flashcolumn chromatography using 95:5 CHCl₃/MeOH as the eluent.

[2043] NMR data was as follows:

[2044]¹H nmr (CDCl₃): δ=8.29 (d, 1H), 7.65 (d, 1H), 7.40-7.20 (m, 5H),7.10 (m, 1H), 6.99 (m,2H), 5.27 (d, 1H), 4.47 (bs, 2H), 4.09 (m, 2H),3.57 and 3.51 (m, 3H), 2.72 (m, 2H), 2.31 (m, 2H), 1.19 (m, 2H).

[2045] Optical Rotation: [α]₂₃=−66° (c 1, MeOH).

[2046] C₂₃H₂₆N₂O₅F₂ (MW 448); mass spectroscopy (MH⁺) 449.

EXAMPLE 188 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4enoate

[2047] Step A—Synthesis of(S)-3-(Hexenoyl)-4-(phenylmethyl)-2-oxazolidinone

[2048] To a mechanically stirred solution of 9.50 g (83.2 mmol, 1.10equiv.) of 4-hexenoic acid (commericially available from Lancaster,Catalog #252-427-6) and 13.9 mL (10.1 g, 99.7 mmol, 1.33 equiv.) oftriethylamine in 150 mL of dry THF, cooled to −78° C. under dry N₂, wasadded 10.71 mL (10.49 g, 87.0 mmol, 1.15 equiv.) of pivaloyl chloride(Aldrich). The mixture was warmed to 0° C. for 60 min, and then recooledto −78° C. A solution of 13.4 g (75.6 mmol, 1.00 equiv) of(S)-(−)-(phenylmethyl)-2-oxazolidone (Aldrich) and 22 mg oftriphenylmethane (indicator) in 150 mL of dry THF, stirred at −30° C. to45° C. under N₂, was treated dropwise with n-butyllithium (˜2.5 M inhexanes) (Aldrich) until an orange color persisted (˜30 mL required).The resulting solution was cooled to −78° C. and then added, via rapidcannulation, to the above stirred mixture containing the mixedanhydride. The residual lithiated oxazolidone was rinsed in with two10-mL portions of dry THF and the resulting mixture was stirred at −78°C. for 1.5 h, and then at 0° C. for 1 h. The mixture was partitionedbetween CH₂Cl₂ and pH 7 phosphate buffer. The CH₂Cl₂ phase was washedwith saturated aqueous NaHCO₃ followed by half-saturated aqueous NaCl,dried (MgSO₄), and evaporated in vacuo. The residual cream-colored solid(22.4 g) was chromatographed (Waters Prep 2000, 5.0 cm×25 cm 10μKromasil KR60-10SIL-5025 column) in two batches eluting with 85:15hexanes/EtOAc. The chromatographed product was recrystallized fromhexane to yield 14.34 g (first crop, 69%) of the title compound as finewhite needles. ¹H NMR (300 MHz, CDCl₃) a 7.37-7.20 (m, 5H, —C₆H₅),5.60-5.43(m, 2H, CH═CHCH₃), 4.71-4.63(m, 1H, NCH(Ph) CH₂0), 4.23-4.14(m,2H, NCH(Ph)CH ₂O), 3.295(dd, J=13.3, 3.3 Hz, 1H, CHHC₆H₅), 3.11-2.90 (m,2H, CH ₂C═O), 2.758 (dd, J=13.3, 9.6 Hz, 1H, CHHC₆H₅), 2.42-2.34 (m, 2H,CH═CHCH ₂), 1.67-1.65 (m, 2H, CH═CHCH ₃).

[2049] Step B—Synthesis of(4S)-3-[(S)-2-Azidohex-4enoyl]-4-(phenylmethyl)-2-oxazolidinone

[2050] A solution of 5.47 g (20.0 mmol, 1.00 equiv) of the product fromStep A above in 60 mL of dry THF, stirred at −78° C. under dry N₂, wasadded via rapid cannulation to a stirred, cooled (−78° C.) solution of43.6 mL (22.0 mmol, 1.10 equiv) of potassium hexamethyldisilazide (0.505M in toluene) (Aldrich) and 60 mL of dry THF. The residual imidesolution was rinsed in with two 5-mL portions of dry THF. The resultingsolution was stirred at −78° C. for 30 min. To the above solution of theK-enolate, stirred at −78° C. under dry N₂, was added a cooled (−78° C.)solution of 7.43 g (24.0 mmol, 1.2 equiv) of trisyl azide (prepared asdescribed in R. E. Harmon et al., J. Org. Chem., 1973, 38, 11-16) in 60mL of dry THF via rapid cannulation. (Note the reaction exothermed to−68° C. during the addition). After 1-2 min, 4.24 mL (4.45 g, 74.1 mmol,3.7 equiv) of glacial acetic acid was added in one portion. Theresulting mixture was stirred at −78° C. for 15 min, and was thenallowed to warm to 25° C. on stirring overnight. The mixture waspartitioned between CH₂Cl₂ and pH 7 phosphate buffer. The aqueous phasewas extracted with CH₂Cl₂ (3×) and the organic extracts were combined,washed with dilute aqueous NaHCO₃, dried (MgSO₄), and evaporated invacua. The residual oil (9.55 g) was chromatographed (Waters Prep 2000,5.0 cm×25 cm 10μ Kromasil KR60-10SIL-5025 column) eluting with a 3 Llinear gradient from 30:70 to 80:20 CH₂Cl₂/hexanes. Afterrechromatographing the mixed fractions (2×), a total of 5.27 g (84%yield) of the title compound (faster eluting, major diastereomer) wasisolated as a colorless, viscous oil. ¹H NMR (300 MHz; CDCl₃) 67.38-7.20 (m, 5H, —C₆H₅), 5.73-5.62 (m, 1H, CH═CHCH₃), 5.52-5.41 (m, 1H,CH═CHCH₃), 5.011 (dd, J=8.3, 5.5 Hz, 1H, CH(N₃) C═O), 4.71-4.63 (m, 1H,NCH(Ph)CH₂O), 4.236 (d, J=5.1 Hz, 2H, NCH(Ph)CH ₂O), 3.338 (dd, J=13.4,3.3 Hz, 1H, CHHC₆H₅), 2.827 (dd, J=13.4, 9.5 Hz, 1H, CHHC₆H₅), 2.64-2.46(m, 2H, CH ₂CH═CHCH₃), 1.694 (dd, J=6.4, 1.1 Hz, 3H, CH═CHCH ₃).

[2051] Step C—Synthesis of (S)-2-Azidohex-4enoic Acid

[2052] A solution of 5.00 g (15.91 mmol) of the product from Step Babove in 240 mL of THF and 80 mL of deionized water, stirred at 0° C.under N₂, was treated with 762 mg (31.8 mmol, 2.00 equiv) of LiOH(anhydrous powder). After stirring at 0° C. for 30 min, 100 mL of 0.5 Naqueous NaHCO₃ was added and the THF was removed by rotary evaporationin vacuo. The residue was diluted to 400-500 mL with H₂O and extractedwith 5 portions of CH₂Cl₂. The aqueous phase was acidified to pH 1-2 bythe cautious addition of 5 N HCl, and then was extracted with 4 portionsof EtOAc. The EtOAc extracts were combined, dried (Na₂SO₄), andevaporated in vacuo to yield 2.45 g (99%) of the title compound as alight amber oil. ¹H NMR (300 MHz, CDCl₃) δ11.38 (br s, 1H, CO₂H),5.73-5.62 (m, 1H, CH₃CH═CH), 5.48-5.38 (m, 1H,CH═CHCH₂), 3.928 (dd,J=7.8, 5.4 Hz, 1H, CH(N₃)CO₂H), 2.66-2.47(m, 2H, CH═CHCH ₂), 1.703 (dd,J=6.4, 1.1 Hz, 3H, CH₃.

[2053] Step D—MethylN-[N-tert-Butoxycarbonyl-L-alaninyl]-(S)-2-aminohex-4-enoate

[2054] A solution of 504.7 mg (3.25 mmol) of the product from Step Cabove in diethyl ether, cooled to 0° C., was treated dropwise withethereal diazomethane (prepared as described in L. F. Fieser et al.,“Reagents for Organic Synthesis”, Vol. 1, p. 191, Wiley & Sons (1967))until a yellow color persisted. The excess diazomethane was removed byentraining with N₂, and the ether was evaporated under a stream of N₂.The residual oil was dissolved in 10 mL of anhydrous methanol. Thesolution was cooled to 0° C. under dry N₂ and 1.24 g (6.54 mmol, 2.0equiv) of anhydrous SnCl₂ was added. The mixture was stirred at ≦25° C.for 4 h, and the solvent was evaporated in vacuo to afford a solidtin-amine complex.

[2055] A solution of 1.23 g (6.50 mmol, 2.00 equiv.) of N-Boc-L-alanine(Sigma) and 0.715 mL (0.658 g, 6.50 mmol, 2.0 equiv.) of4-methylmorpholine (redistilled, 99.5%) (Aldrich) in 15 mL of anhydrousTHF, cooled to −15 to −20° C. under dry N₂, was treated dropwise with0.861 mL (0.907 g, 6.50 mmol, 2.00 equiv.) of iso-butyl chloroformate(Aldrich). After stirring at −15 to −20° C. for 20 min, the resultingmixture containing the mixed anhydride was added via cannulation to thesolid tin-amine complex (vide supra). The residual mixed anhydride wasrinsed in with 7 mL of THF and 1.1 g (13.1 mmol, 4.0 equiv.) of NaHCO₃powder and 5 mL of H₂O was added. The mixture was stirred at 0° C. for 5h. An additional 1.1 g (13.1 mmol, 4.0 equiv.) of NaHCO₃ powder and 5 mLof H₂O was added and the mixture was stirred at 20° C. for 1.5 h. Themixture was filtered to remove the gelatinous precipitate, and thefilter cake was washed with several portions of EtOAc. The filtrate waswashed with saturated aqueous NaHCO₃ (the aqueous phase wasback-extracted with 3 portion of EtOAc), followed by pH 4-5 phosphatebuffer (the aqueous phase was back-extracted with 3 portions of EtOAc).The organic phase was dried (Na₂SO₄) and evaporated in vacuo. Theresidual straw colored oil (1.21 g) was chromatographed (Waters Prep2000, 5.0 cm×25 cm 10μ Kromasil KR60-10SIL-5025 column) eluting with a3-L linear gradient from 80:20 to 40:60 hexane/EtOAc to yield 0.9088 g(89%) of the title compound as a white solid. Tlc R_(f) 0.25 [silica,hexane/EtOAc 6:4)]; ¹H NMR (300 MHz, CDCl₃) δ6.61 (d, J=7.6 Hz, 1H, NH),5.60-5.48(m, 1H, CH═CHCH₃), 5.33-5.23 (m, 1H, CH═CHCH₃), 5.08 (d, J=7.3Hz, 1H, NH), 4.591 (dt, J_(d)=7.8 Hz, J_(t)=5.7 Hz, 1H,HNCH(CH₂CH═CHCH₃)), 4.19 (br m, 1H, HNCH(CH₃), 3.74(s, 3H, OCH₃),2.56-2.39 (sym m, 2H, CH ₂CH═CHCH₃), 1,658 (dd, J=6.4, 1.2 Hz, 3H,CH₂CH═CHCH ₃), 1.454 (s, 9H, OC(CH₃)₃), 1.358 (d, J=7.1 Hz, 3H,HNCH(CH₃)).

[2056] Step E—Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate

[2057] A solution of 0.811 g (2.58 mmol) of the product from Step Dabove in 5 mL of CH₂Cl₂ was cooled to 0° C. under dry N₂ and 5 mL oftrifluoroacetic acid was introduced by syringe at <4° C. The solutionwas stirred at 0° C. for 40 min. Toluene (15 mL) was added and themixture was evaporated in vacuw on the rotary evaporator. The additionof toluene and solvent evaporation was repeated. The residue wasdissolved in 20 mL of CH₂Cl₂ and the solution was cooled to 0° C. underdry N₂. To this was added 1.35 mL (1.00 g, 7.74 mmol, 3.0 equiv) ofethyldiisopropylamine (Aldrich), followed by the dropwise addition at≦6° C. of 0.728 mL (0.938 g, 5.16 mmol, 2.0 equiv) of3,5-difluorophenylacetyl chloride (prepared from3,5-difluorophenylacetic acid (Aldrich) using General Procedure H′). Theresulting solution was stirred at 0° C. for 2 h. Excess saturatedaqueous NaHCO₃ was added and the two phase mixture was stirred in an icebath for 30 min. The mixture was diluted with CH₂Cl₂ and washedsuccessively with aqueous NaHCO₃/Na₂CO₃ (pH 10), 1 N aqueous NaHSO₄, andsaturated aqueous NaCl. The CH₂Cl₂ solution was dried (Na₂SO₄) andevaporated in vacuo to afford 1.17 g of a yellow solid. This wasrecrystallized from EtOAc to yield 602 mg (63 %) of the title compoundas a fluffy white solid. This material was found by 300 mHz tH NMRanalysis to consist of a 92:8 mixture of E and Z isomers, respectively.

[2058] NMR data was as follows:

[2059]¹H nmr (300 MHz, CDCl₃): δ=6.85-6.69 (m, 3H), 6.335 (br d, J=7.8Hz, 1H), 6.289 (br d, J=7.0 Hz, 1H), 5.58-5.47 (m, 1H), 5.28-5.18 (m,1H), 4.58-4.45 (m, 2H) 3.745 (s, 3H), 3.528 (s, 2H), 2.457 (apparent t,J=6.4 Hz, 2H), 1.650 (dd, J=6.5, 1.3Hz, 3H), 1.58 (dm, J=6.5 Hz, 0.08H),1.375 (d, J=7.0 Hz, 3H).

[2060] IR (CHCl₃) 3421, 1742, 1667, 1626, 1597, 1503, and 1120 cm⁻¹

[2061] Anal. Calcd for C₁₈H₂₂F₂N₂O₄: C, 58.69; H, 6.02; N, 7.60. Found:C, 58.83, H, 5.89; N, 7.67.

[2062] C₁₈H₂₂F₂N₂O₅ (MW=368); mass spectroscopy (MH⁺) 368.

EXAMPLE 189 Synthesis ofN-[N-(Cyclopropylacetyl)-L-alaninyl]-L-phenylglycine tert-Butyl Ester

[2063] Following General Procedure U and using cyclopropylacetic acid(Lancaster) and N-(L-alaninyl)-L-phenylglycine tert-butyl ester (GeneralProcedure U of Z-alanine (Bachem) to phenylglycine-t-butyl (Novabio) andthen General Procedure O), the title compound was prepared as a solid(mp=105-107° C.). The reaction was monitored by tlc (Rf=0.33 in 1:1EtOAc/hexane, 0.13 in 5% MeOH/DCM).

[2064] NMR data was as follows:

[2065]¹H nmr (CDCl₃): δ=0.15 (m, 2H), 0.56 (m, 2H), 0.91 (m, 1H), 1.38(m, 12H), 2.09 (d, J=7.1 Hz, 2H), 4.62 (m, 1H), 5.39 (d, J=7.2 Hz, 1H),6.52 (d, I=7.2 Hz, 1H), 7.31 (m, 6H).

[2066]¹³C-nmr (CDCl₃): δ=4.53, 4.55, 6.9, 18.4, 27.8, 41.2, 48.4, 57.1,82.6, 127.0, 128.2, 128.7, 136.8, 169.4, 171.4, 172.3.

[2067] C₂₀H₂₈N₂O₄ (MW=360.46); mass spectroscopy (MH⁺) 361.

EXAMPLE 190 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(4phenylphenyl)acetamide

[2068] Following General Procedure AB and using3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and4-biphenylcarboxaldehyde (Aldrich), the title compound was prepared as asolid (mp=266-267° C.). The product was purified by recrystallizationfrom EtOAc and/or EtOAc/hexanes.

[2069] NMR data was as follows:

[2070]¹H nmr (DMSO-d₆): δ=8.42 (d, 1H, J=7 Hz) , 8.31 (d, 1H, J=7 Hz),7.91 (s, 1H), 7.6-7.56 (m, 4H) , 7.42-7.59 (m, 5H), 7.2-7.69 (m, 3H),5.42 (d, 1H, J=8 Hz), 4.42 (pentet, 1H, J=8 Hz), 3.5 (s, 1H) , 1.2(doublet on top of a singlet, 12H).

[2071] C₂₉H₃₁N₃O₃F₂ (MW=508); mass spectroscopy (MH⁺) 508.4.

EXAMPLE 191 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycinetert-Butyl Ester

[2072] Following General Procedure D and using 3,5-difluorophenylaceticacid (Aldrich) and N-[(S)-2-aminobutanoyl]-L-phenylglycine tert-butylester (from Example D13 above), the title compound was prepared as asolid (mp=138.7-140.0° C.). The reaction was monitored by tlc (Rf=0.24in 2/1 hexanes:EtOAc) and the product was purified by flashchromromatography and HPLC.

[2073] NMR data was as follows:

[2074]¹H-nmr (DMSO-d₆, 250 MHz): δ=8.66 (d, J=6.75 Hz, 1H), 8.30 (d,J=8.26 Hz, 1H), 7.37 (bs, 5H), 7.11-6.96 (m, 3H), 5.23 (d, J=7.00 Hz,1H), 4.36 (td, J=7.88, 5.50 Hz, 1H), 3.53 (AB_(q), J_(AB)=14.05 Hz,ΔV_(AB)=7.75 Hz, 2H), 1.85-1.48 (m, 2H), 1.34 (s, 9H), 0.88 (t, J=7.38Hz, 3H).

[2075] Optical Rotation: [α]₂₀=21.8° (c 1.0, MeOH).

[2076] C₂₄H₂₈N₂O₄F₂ (MW=446.50); mass spectroscopy (MH+, minus CO₂-tBu)345.2.

EXAMPLE 192 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-ButylEster

[2077] Following General Procedure D and using 3,5-difluorophenylaceticacid (Aldrich) and N-(L-valinyl)-L-phenylglycine tert-butyl ester (fromExample D14 above), the title compound was prepared as a solid(mp=170.5-171.8° C.). The reaction was monitored by tlc (Rf=0.39 in 2:1hexanes/EtOAc) and the product was purified by flash chromromatographyand HPLC.

[2078] NMR data was as follows:

[2079]¹H nmr (DMSO-d₆, 250 MHz): δ=8.71 (d, J=6.75 Hz, 1H), 8.22 (d,J=9.26 Hz, 1H), 7.37 (bs, 5H), 7.11-6.96 (m, 3H), 5.23 (d, J=6.50 Hz,1H), 4.36 (dd, J=8.88, 6.38 Hz, 1H), 3.55 (AB_(q), J_(AB)=13.88 Hz,ΔV_(AB)=21.56 Hz, 2H), 2.10-1.95 (m, 1H), 1.34 (s, 9H), 0.88 (d, J=6.75Hz, 3H), 0.86 (d, J=6.50 Hz, 3H).

[2080] Optical Rotation: [α]₂₀=20.8° (c 1.0, MeOH).

[2081] C₂₅H₃₀N₂O₄F₂ (MW=460.53); mass spectroscopy (MH+, minus CO₂-tBu)359.2.

EXAMPLE 193 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-methioninyl]-L-phenylglycine MethylEster

[2082] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(L-methioninyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-methionine (Sigma) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=189.3° C.).The reaction was monitored by tlc (Rf=0.53 in 5:95 MeOH/CH₂Cl₂) and theproduct was purified by recrystallization from ethyl acetate/hexanes.

[2083] NMR data was as follows:

[2084]¹H-nmr (DMSO-d₆): δ=8.85 (d, J=6.7 Hz, 1H), 8.41 (d, J=8.1 Hz,1H), 7.38 (m, 5H), 7.09 (m, 1H), 6.98 (m, 2H), 5.38 (d, J=6.6 Hz, 1H),4.47 (m, J=8.2 Hz, 1H), 3.62 (s, 3H), 3.51 (d, 2H), 2.46 (t, 2H), 2.04(s, 3H), 1.89 (m, 2H).

[2085]¹³C-nmr (DMSO-d₆): δ=172.036, 171.729, 169.883, 164.658, 164.479,161.406, 161.227, 141.689, 141.557, 141.427, 136.524, 129.512, 129.213,128.717, 126.274, 113.187, 113.085, 112.961, 112.862, 103.023, 102.684,102.340, 93.065, 57.205, 53.063, 42.231, 33.075, 30.221, 15.465.

[2086] C₂₂H₂₄N₂O₄F₂S (MW=450.51); mass spectroscopy (MH⁺) 450.

EXAMPLE 194 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-valinyl]-L-phenylglycine Methyl Ester

[2087] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(L-valinyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-valine (Sigma) and L-phenylglycinemethyl ester hydrochloride (Aldrich) using General Procedure E, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=226.5° C.). The reaction wasmonitored by tlc (Rf=0.49 in 5:95 MeOH/CH₂Cl₂) and the product waspurified by flash chromatography using MeOH/CH₂Cl₂ as the eluent.

[2088] NMR data was as follows:

[2089]¹H-nmr (DMSO-d₆): δ=8.84 (d, J=6.2 Hz, 1H), 8.23 (d, J=8.8 Hz,1H), 7.38 (m, 5H), 7.07 (m, 1H), 6.98 (m, 2H), 5.37 (d, J=6.5 Hz, 1H),4.34 (m, J=8.9 Hz, 1H), 3.55 (m, 5H), 2.01 (m, 1H), 0.87 (m, 6H).

[2090]¹³C-nmr (DMSO-d₆): δ=171.988, 171.690, 169.861, 164.633, 164.456,161.382, 161.204, 141.987, 141.859, 141.727, 136.553, 129.470, 129.192,128.791, 113.128, 113.026, 112.902, 112.803, 102.961, 102.619, 102.281,57.914, 57.262, 52.935, 42.274, 31.728, 19.845, 18.815.

[2091] C₂₂H₂₄N₂O₄F₂ (MW=418.44); mass spectroscopy (MH⁺) 418.1.

EXAMPLE 195 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine MethylEster

[2092] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(2-aminobutanoyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-aminobutyric acid (Sigma) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=215.3° C.).The reaction was monitored by tlc (Rf=0.46 in 5:95 MeOH/CH₂Cl₂) and theproduct was purified by recrystallization from ethyl acetate/hexanes.

[2093] NMR data was as follows:

[2094]¹H-nmr (DMSO-d₆): δ=8.83 (d, J=6.8 Hz, 1H), 8.32 (d, J=8.1 Hz,1H), 7.38 (m, 5H), 7.08 (m, 1H), 6.98 (m, 2H), 5.38 (d, J=6.8 Hz, 1H),4.35 (m, J=7.9 Hz, 1H), 3.61 (s, 3H), 3.52 (d, 2H), 1.64 (m, 2H), 0.88(t, 3H).

[2095]¹³C-nmr (DMSO-d₆): δ=171.684, 170.934, 168.984, 164.193, 163.980,160.295, 160.083, 141.059, 140.902, 140.743, 135.857, 128.689, 128.372,127.892, 112.387, 112.257, 112.131, 111.999, 102.254, 101.845, 101.438,56.351, 53.441, 52.212, 41.436, 25.675, 10.067.

[2096] C₂₁H₂₂N₂O₄F₂ (MW=404.42); mass spectroscopy (MH⁺) 405.1.

EXAMPLE 196 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-leucinyl]-L-phenylglycine Methyl Ester

[2097] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(L-leucinyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-leucine (Aldrich) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=178.4° C.).The reaction was monitored by tlc (Rf=0.51 in 5:95 MeOH/CH₂Cl₂) and theproduct was purified by flash chromotograph using MeOH/CH₂Cl₂ as theeluent.

[2098] NMR data was as follows:

[2099]¹H-nmr (DMSO-d₆): δ=8.85 (d, J=6.8 Hz, 1H), 8.33 (d, J=8.3 Hz,1H), 7.37 (m, 5H), 7.08 (m, 1H), 6.95 (m, 2H), 5.37 (d, J=6.8 Hz, 1H),4.46 (m, J=8.3 Hz, 1H), 3.60 (s, 3H), 3.49 (d, 2H), 1.55 (m, 3H), 0.89(d, 3H), 0.82 (d, 3H).

[2100]¹³C-nmr (DMSO-d₆): δ=172.225, 170.899, 168.888, 164.197, 163.984,160.298, 160.086, 141.029, 140.887, 140.723, 135.875, 128.657, 128.348,127.944, 112.340, 112.207, 112.084, 111.951, 102.251, 101.842, 101.435,56.343, 52.214, 50.697, 41.510, 40.982, 24.449, 23.056, 21.575.

[2101] C₂₃H₂₆N₂O₄F₂ (MW=432.47); mass spectroscopy (MH⁺) 432.1.

EXAMPLE 197 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-Lphenylalaninyl]-L-phenylglycine MethylEster

[2102] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(L-phenylalaninyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-phenylalanine (Aldrich) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=188.3° C.).The reaction was monitored by tlc (Rf=0.59 in 5:95 MeOH/CH₂Cl₂) and theproduct was purified by flash chromotography using MeOH/CH₂Cl₂ as theeluent.

[2103] NMR data was as follows:

[2104]¹H nmr (DMSO-d₆): δ=8.99 (d, J=6.9 Hz, 1H), 8.44 (d, J=8.6 Hz,1H), 7.4 (m, 5H), 7.21 (m, 5H), 7.03 (m, 1H), 6.77 (m, 2H), 5.42 (d,J=6.9 Hz, 1H), 4.70 (m, J=8.5 Hz, 1H), 3.63 (s, 3H), 3.40 (m, 2H), 3.08(m, 1H), 2.76 (m, 1H).

[2105]¹³C-nmr (DMSO-d₆): δ=171.428, 170.896, 168.853, 164.127, 163.915,160.222, 160.010, 140.756, 140.601, 140.438, 137.662, 135.918, 130.638,129.247, 128.737, 128.415, 127.908, 126.281, 112.147, 112.025, 111.892,102.189, 101.782, 101.373, 56.411, 53.461, 52.306, 41.513, 37.796.

[2106] C₂₆H₂₄N₂O₄F₂ (MW=466.49); mass spectroscopy (MH⁺) 466.

EXAMPLE 198 Synthesis ofN-[N-(3,5Difluorophenylacetyl)glycinyl]-L-phenylglycine Methyl Ester

[2107] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(glycinyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-glycine (Aldrich) and L-phenylglycinemethyl ester hydrochloride (Aldrich) using General Procedure E, followedby removal of the BOC-group using General Procedure P), the titlecompound was prepared as a solid (mp=142.3° C.). The reaction wasmonitored by tlc (Rf=0.33 in 5:95 MeOH/CH₂Cl₂) and the product waspurified by recrystallization from diethyl ether/hexanes.

[2108] NMR data was as follows:

[2109]¹H nmr (DMSO-d₆): δ=8.82 (d, J=7.2 Hz, 1H), 8.39 (t, 1H), 7.37 (m,5H), 7.05 (m, 3H), 5.44 (d, 7.1 Hz, 1H), 3.83 (d, 2H), 3.62 (s, 3H),3.53 (s, 2H).

[2110]¹³C-nmr (DMSO-d₆): δ=170.956, 169.427, 168.788, 164.226, 164.013,160.329, 160.115, 140.817, 140.663, 140.499, 136.222, 128.728, 128.338,127.687, 112.494, 112.360, 112.238, 112.104, 102.310, 101.900, 101.492,56.200, 52.321, 41.731, 41.464.

[2111] C₁₉H₁₈N₂O₄F₂ (MW=376.36); mass spectroscopy (MH⁺) 376.0.

EXAMPLE 199 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine MethylEster

[2112] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-(L-phenylglycinyl)-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-phenylglycine (Novabiochem) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure AH, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=222.8° C.).The reaction was monitored by tlc (Rf=0.61 in 5:95 MeOH/CH₂Cl₂) and theproduct was purified by recrystallization from ethyl acetate.

[2113] NMR data was as follows:

[2114]¹H nmr (DMSO-d₆): δ=9.22 (d, J=6.8 Hz, 1H), 8.85 (d, J=8.2 Hz,1H), 7.37 (m, 10H), 7.08 (m, 1H), 6.97 (d, 2H), 5.69 (d, J=8.2 Hz, 1H),5.43 (d, J=6.8 Hz, 1H1), 3.61 (d, 2H), 3.55 (s, 3H).

[2115]¹³C-nmr (DMSO-d₆): δ=170.606, 169.727, 168.777, 164.194, 163.982,160.296, 160.082, 140.920, 140.757, 140.603, 138.391, 135.900, 128.732,128.425, 128.233, 127.871, 127.556, 127.222, 112.467, 112.340, 112.209,112.082, 102.292, 101.884, 101.475, 56.431, 55.621, 52.203, 41.205.

[2116] C₂₅H₂₂N₂O₄F₂ (MW=452.46); mass spectroscopy (MH⁺) 452.2.

EXAMPLE 200 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-alanineMethyl Ester

[2117] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-alanine methylester hydrochloride (Aldrich), the title compound was prepared as asolid (mp=140.5-142° C.). The reaction was monitored by tlc (Rf=0.17 in50% EtOAc/hexanes).

[2118] NMR data was as follows:

[2119]¹H-nmr (CDCl₃): δ=1.3-1.4 (m, 6H), 3.55 (s, 2H), 3.75 (s, 3H:),4.4-4.6 (m, 21H), 6.1-6.3 (brd, 11H), 6.6-6.7 (brd, 1H), 7.2-7.4 (m,5H).

[2120]¹³C-nmr (CDCl₃): δ=18.4, 19.0, 44.1, 48.6, 49.3, 53.0, 127.9,129.5, 129.8, 135.1, 171.5, 172.4, 173.6.

[2121] C₁₅H₂₀N₂O₄ (MW=292.34); mass spectroscopy (MH⁺) 293.

EXAMPLE 201 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-leucineMethyl Ester

[2122] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1above) and L-leucine methylester hydrochloride (Aldrich), the title compound was prepared as asolid (mp=102.5-105° C.). The reaction was monitored by tlc (Rf=0.25 in50% EtOAc/hexanes).

[2123] NMR data was as follows:

[2124]¹H nmr (CDCl₃): δ=0.8-0.95 (m, 6H), 1.3 (d, J=7 Hz, 3H), 1.4-1.6(m, 3H), 3.58 (s, 2H), 3.75 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, 1H), 6.7(brd, 1H), 7.2-7.4 (m, 5H).

[2125]¹³C-nmr (CDCl₃): δ=18.7, 22.3, 23.4, 25.3, 41.5, 44.1, 49.2, 51.4,52.8, 127.9, 129.5, 129.8, 135.0, 171.5, 172.6, 173.7.

[2126] C₁₈H₂₆N₂O₄ (MW=334.42); mass spectroscopy (MH⁺) 335.

EXAMPLE 202 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-isoleucineMethyl Ester

[2127] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-isoleucinemethyl ester hydrochloride (Sigma), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.24 in 50% EtOAc/hexanes).

[2128] NMR data was as follows:

[2129]¹H nmr (CDCl₃): δ=0.8-0.95 (m, 6H), 1.0-1.2 (m, 1H), 1.2-1.4 (mincluding 1.3 (d, J=7 Hz, 4H)), 1.8-1.9 (m, 1H), 3.58 (s, 2H), 3.75 (s,3H), 4.4-4.6 (m, 2H), 6.2 (brd, 1H), 6.7 (brd, 1H), 7.2-7.4 (m, 5H).

[2130]¹³C-nmr (CDCl₃): δ=12.1, 16.0, 18.5, 25.6, 38.1, 44.1, 49.3, 52.7,57.2, 127.9, 129.6, 129.8, 135.0, 171.5, 172.5, 172.6.

[2131] C₁₈H₂₆N₂O₄ (MW=334.42); mass spectroscopy (MH⁺) 335.

EXAMPLE 203 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-prolineMethyl Ester

[2132] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-proline methylester hydrochloride (Bachem), the title compound was prepared as an oil.The reaction was monitored by tlc (Rf=0.12 in 50% EtOAc/hexanes).

[2133] NMR data was as follows:

[2134]¹H nmr (CDCl₃): δ=1.33 (d, J=7 Hz, 3H), 1.9-2.1 (m, 3H), 2.1-2.25(m, 1H), 3.5-3.8 (m including 3.58 (s) and 3.75 (s), total 7H), 44.4 (m,1H), 4.74.8 (m, 1H), 6.5 (brd, 1H), 7.2-7.4 (m, 5H).

[2135]¹³C-nmr (CDCl₃): δ=18.5, 25.5, 29.5, 44.1, 47.3, 47.4, 52.8, 59.3,127.8, 129.42, 129.48, 129.9, 135.2, 170.9, 171.8, 172.8.

[2136] C₁₇H₂₂N₂O₄ (MW=318.38); mass spectroscopy (MH⁺) 319.

EXAMPLE 204 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-phenylalanineMethyl Ester

[2137] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-phenylalaninemethyl ester hydrochloride (Aldrich), the title compound was prepared asa solid (mp=148-149.5° C.). The reaction was monitored by tlc (Rf=0.24in 50% EtOAc/hexanes) and the product was not purified.

[2138] NMR data was as follows:

[2139]¹H nmr (CDCl₃): δ=1.25 (d, J=7 Hz, 3H), 3.02 (dd, J=7, 14Hz, 1H),3.12 (dd, J=5, 14 Hz, 1H), 3.53 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 1H),4.75- 4.85 (m, 1H), 5.9 (brd, 1H), 6.5 (brd, 1H), 7.0-7.5 (m, 10H).

[2140]¹³C-nmr (CDCl₃): δ=18.6, 38.3, 44.0, 49.2, 52.9, 53.9, 127.7,128.0, 129.1, 129.6, 129.8, 129.9, 135.0, 136.3, 171.4, 172.2, 172.3.

[2141] C₂₁H₂₄N₂O₄ (MW=368.44); mass spectroscopy (MH⁺) 369.

EXAMPLE 205 Synthesis ofN-[N-(Phenylacetyl)-L-alaninyl]-N-(tert-butoxycarbonyl)-L-lysine MethylEster

[2142] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) andN,-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride (Bachem),the title compound was prepared as a solid (mp=119-121° C.). Thereaction was monitored by tlc (Rf=0.46 in 90:10:1 CH₂Cl₂MeOHNH₄OH).

[2143] NMR data was as follows:

[2144]¹H-nmr (CDCl₃): δ=1.2-1.9 (m, 18H)(includes 1.3 (d, J=7 Hz) and1.4 (s)), 3.0-3.15 (m, 2H), 3.12 (dd, J=5, 14 Hz, 1H), 3.57 (s, 2H),3.72 (s, 3H), 4.4-4.5 (m, 2H), 4.75-4.85 (m, 1H), 6.2 (brd, 1H), 6.75(brd, 1H), 7.2-7.4 (m, 5H).

[2145]¹³C-nmr (CDCl₃): δ=18.6, 22.9, 29.0, 29.9, 32.0, 40.5, 44.0, 49.4,52.7, 53.0, 79.8, 127.9, 129.5, 129.8, 135.1, 156.7, 171.6, 172.7,173.0.

[2146] C₂₃H₃₅N₃O₆ (MW=449.55); mass spectroscopy (MH⁺)=450.

EXAMPLE 206 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]glycine MethylEster

[2147] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and glycine methylester hydrochloride (Aldrich), the title compound was prepared as asolid (mp=152-153.5° C.). The reaction was monitored by tlc (Rf=0.10 in505% EtOAc/hexanes).

[2148] NMR data was as follows:

[2149]¹H nmr (CDCl₃): δ=1.33 (d, J=7 Hz, 3H), 3.59 (s, 2H), 3.75 (s,3H), 3.97 (d, J=6.5 Hz, 2H), 4.5-4.6 (m, 1H), 6.1 (brd, 1H), 6.8 (brs,1H), 7.2-7.6 (m, 5H).

[2150]¹³C-nmr (CDCl₃): δ=18.7, 41.6, 43.9, 49.2, 52.9, 127.9, 129.5,129.9, 135.0, 170.6, 171.7, 173.2.

[2151] C₁₄H₁₈N₂O₄ (MW=278.31); mass spectroscopy (MH⁺) 279.

EXAMPLE 207 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-valine MethylEster

[2152] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (fromo Example B1 above) and L-valine methylester hydrochloride (Aldrich), the title compound was prepared as asolid (mp=112-115° C.). The reaction was monitored by tlc (Rf=0.33 in50% EtOAc/hexanes) and the product was not purified.

[2153] NMR data was as follows:

[2154]¹H nmr (CDCl₃): δ=0.8-0.9 (overlapping d appearing as t, J=6 Hz,6H), 2.0-2.2 (m, 1H), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 1H),4.5-4.65 (m, 1H), 6.2 (brd, 1H), 6.75 (brd, 1H), 7.2-7.4 (m, 5H).

[2155]¹³C-nmr (CDCl₃): δ=18.3, 18.5, 19.5, 31.5, 44.1, 49.3, 52.7, 57.9,127.9, 129.5, 129.8, 135.0, 171.5, 172.7, 172.7.

[2156] C₁₇H₂₄N₂O₄ (MW=320.39); mass spectroscopy (MH⁺) 321.

EXAMPLE 208 Synthesis of MethylN-[N-(Phenylacetyl)-L-alaninyl]-2-(S)-aminobutanoate

[2157] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and methylL-2-aminobutanoate hydrochloride (prepared from L-2-aminobutanoic acid(Bachem) using General Procedure H (without extractions)), the titlecompound was prepared as a solid (mp=120° C.). The reaction wasmonitored by tlc (Rf=0.2 in 50% EtOAc/hexanes).

[2158] NMR data was as follows:

[2159]¹H nmr (CDCl₃): δ=0.85 (t, J=6 Hz, 3H), 1.32 (d, J=7 Hz, 3H), 1.6-1.9 (m, 2H), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.6 (m, 2H), 6.2 (brd, 1H),6.75 (brd, 1H), 7.2-7.4 (m, 5H).

[2160]¹³C-nmr (CDCl₃): δ=10.2, 18.9, 25.8, 44.0, 49.3, 52.8, 54.0,127.9, 129.5, 129.8, 135.1, 171.5, 172.7, 173.0.

[2161] C₁₆H₂₂N₂O₄ (MW=306.36); mass spectroscopy (MH⁺) 307.

EXAMPLE 209 Synthesis of MethylN-[N-(Phenylacetyl)-L-alaninyl]-2-(S)-aminopentanoate

[2162] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and methyl2-(S)-aminopentanoate hydrochloride (prepared from L-2-aminovaleric acid(Bachem) using General Procedure H (without extractions)), the titlecompound was prepared as a solid (mp=135-137° C.). The reaction wasmonitored by tlc (Rf=0.30 in 50% EtOAc/hexanes).

[2163] NMR data was as follows:

[2164]¹H nmr (CDCl₃): δ=0.87 (t, J=6 Hz, 3H), 1.2-1.4 (m with d, J=7 Hz,5H), 1.5-1.8 (m, 2H), 3.57 (s, 2H), 3.72 (s, 3H), 4.4-4.5 (m, 2H), 6.4(brd, 1H), 7.0 (brd, 1H), 7.2-7.4 (m, 5H).

[2165]¹³C-nmr (CDCl₃): δ=14.2, 19.0, 19.2, 34.5, 44.0, 49.2, 52.7, 52.8,127.8, 129.4, 129.8, 135.2, 171.5, 172.8, 173.3.

[2166] C₁₇H₂₄N₂O₄ (MW=320.39); mass spectroscopy (MH⁺) 321.

EXAMPLE 210 Synthesis of N-[N-(3-Nitrophenylacetyl)-L-alaninyl]-L-valine

[2167] Following General Procedure AF and usingN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl ester (fromExample 143 above), the title compound was prepared as a solid. Thereaction was monitored by tlc (Rf=0.05 in 9:1 CHCl₃/MeOH).

[2168] NMR data was as follows:

[2169]¹H-nmr (DMSO-d₆): δ=8.41 (d, 1H), 8.13 (s, 1H), 8.09 (d, 1H), 7.91(d, 1H), 7.68 (d, 1H), 7.56 (t, 1H), 4.4 (m, 1H), 4.10 (m, 1H), 3.63 (s,2H), 2.01 (m, 1H), 1.19 (m, 3H), 0.89 (d, 6H).

[2170] Optical Rotation: [α]₂₃=−49° (c 1, MeOH).

[2171] C₁₆H₂₁N₃O₆ (MW=351.3); mass spectroscopy (MH⁺) 352.

EXAMPLE 211 Synthesis ofN-[N-(Phenylacetyl)-L-alaninyl]-L-N-methylalanine Methyl Ester

[2172] Following General Procedure A and usingN-(phenylacetyl)-L-alanine (from Example B1 above) and L-N-methylalaninemethyl ester hydrochloride (prepared from L-N-methylalaninehydrochloride (Bachem) using General Procedure H (without extractions)),the title compound was prepared as an oil. The reaction was monitored bytlc (Rf=0.13 in 50% EtOAc/hexanes) and the product was purified bycolumn chromatography using 60% EtOAc/hexanes as the eluent.

[2173] NMR data was as follows:

[2174]¹H nmr (CDCl₃): δ=1.2-1.6 (m including 1.32 (d, J=7 Hz, 6H), 2.97(s (rotomers), 3H), 3.57 (s, -2H), 3.7-3.8 (s (rotomers), 3H), 4.4-5.2(m, 2H), 6.6 (brd, 1H), 7.2-7.4 (m, 5H).

[2175]¹³ C-nmr (CDCl₃): δ=14.7, 15.0, 18.8, 19.1, 31.6, 32.3, 44.3,46.2, 46.3, 52.7, 52.88, 52.93, 53.6, 127.81, 127.85, 129.45, 129.48,129.9, 135.2, 170.60, 170.67, 172.19, 172.4, 173.25. 173.31.

[2176] C₁₆H₂₂N₂O₄ (MW=306.36); mass spectroscopy (MH⁺) 307.

EXAMPLE 212 Synthesis of N-[N-(Isovaleryl)-L-phenylglycinyl]-L-alanineIsobutyl Ester

[2177] Following General Procedure C and usingN-(isovaleryl)-L-phenylglycine (prepared from isovaleric acid (Aldrich)and L-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by hydrolysis using General Procedure AF) andL-alanine isobutyl ester hydrochloride (prepared from N-BOC-L-alanine(Sigma) and 2-methyl-1-propanol (Aldrich) using General Procedure C(with catalystic DMAP), followed by removal of the BOC-group usingGeneral Procedure P), the tide compound was prepared as a solid(mp=181-186° C.). The reaction was monitored by tlc (Rf=0.4 in 1:1EtOAc/hexanes) and the product was purified by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluent.

[2178] NMR data was as follows:

[2179]¹H nmr (CDCl₃): δ=1.31 (d, 3H), 5.59 (d, 1H).

[2180] Optical Rotation: [α]₂₀+19° ( 589 nm (c 1.03, DMSO).

[2181] C₂₀H30N₂O₄ (MW=362); mass spectroscopy (MH⁺) 363.

EXAMPLE 213 Synthesis of N-[N-(Isovaleryl)-Lisoleucinyl]-L-alanineIsobutyl Ester

[2182] Following General Procedure C and usingN-(isovaleryl)-L-isoleucine (prepared from isovaleric acid (Aldrich) andL-isoleucine methyl ester hydrochloride (Aldrich) using GeneralProcedure C, followed by hydrolysis using General Procedure AF) andL-alanine isobutyl ester hydrochloride (prepared from N-BOC-L-alanine(Sigma) and 2-methyl-1-propanol (Aldrich) using General Procedure C(with catalystic DMAP), followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid (mp142-146° C.). The reaction was monitored by tlc (Rf=0.4 in 1:1EtOAc/hexanes) and the product was purified by silica gel chromatographyusing 1:1 EtOAc/hexanes as the eluent to provide a 1:4 mixture ofdiastereomers.

[2183] NMR data was as follows:

[2184]¹H nmr (DMSO-d₆): δ=1.26 (d, 3H), 7.70 (d, 1H), 7.80 (d, 1H), 8.30(d, 1H), 8.40 (d, 1H).

[2185] C₁₈H₃₄N₂O₄ (MW=342.48); mass spectroscopy (MH⁺) 343.

EXAMPLE 214 Synthesis ofN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[2186] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-cyclohexyl-L-phenylglycinamide (prepared from N-BOC-L-phenylglycine(Advanced Chemtech) and cyclohexylamine (Aldrich) using GeneralProcedure M, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid. The reactionwas monitored by tlc (Rf=0.5 in 9:1 CHCl₃/MeOH) and the product waspurified by trituration from ethanol.

[2187] NMR data was as follows:

[2188]¹H nmr (CDCl₃): δ=8.55 (m, 2H), 8.08 (d, 1H), 7.30 (m, 5H), 7.08(m, 1H), 6.97 (d, 2H), 5.37 (m, 1H), 3.47 (s, 2H), 1.8-1.6 (m, 6H),1.2340.98 (m, 7H).

[2189] Optical Rotation: [α]₂₃=−32.7° (c 1, MeOH).

[2190] C₂₅H₂₉F₂N₃O₃ (MW=457); mass spectroscopy (MH⁺) 458.

EXAMPLE 215 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4hydroxyproline EthylEster

[2191] Following General Procedure F and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-4-hydroxyproline ethyl ester hydrochloride (Pfaltz & Bauer), the titlecompound was prepared as a foam. The reaction was monitored by tlc(Rf=0.32 in 95:5 CH₂Cl₂/MeOH) and the product was purified by flashcolumn chromatography.

[2192] NMR data was as follows:

[2193]¹H nmr (CDCl₃, 250 Mz): δ=7.31 (d, 1H, J=7.00 Hz), 6.83-6.64 (m,3H), 4.67 (p, 1H, J=7.09 Hz), 4.58 (t, 1H, J=8.26 Hz), 4.47 (bs, 1H),4.25- 4.06 (m, 2H), 3.81 (bd, 1H, J=11.01 Hz), 3.62 (dd, 1H, J=10.76,3.75 Hz), 3.46 (s, 2H), 2.30 (dd, 1H, J=13.51, 8.26 Hz), 1.96 (ddd, 1H,J=13.44, 8.82, 4.56 Hz), 1.33 (d, 3H, J=6.75 Hz), 1.24 (t, 3H, J=7.13Hz).

[2194] C₁₈H₂₃F₂N₂O₅ (MW=384.38); mass spectroscopy (MH⁺) 385.1.

EXAMPLE 216 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-lysine Methyl Ester

[2195] Following General Procedure Y and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N_(ε)-(tert-butoxycarbonyl)-L-lysinemethyl ester (from Example 43 above), the title compound was prepared asan oil. The title compound was isolated as the trifluoroacetic acid salt(containing about 5% excess trifluoroacetic acid).

[2196] NMR data was as follows:

[2197]¹H nmr (CDCl₃+2 drops of CD₃OD): δ=6.40-6.52 (m, 3H), 4.17 (t,1H), 4.40 (q, 1H), 3.42 (s, 3H), 3.23 (s, 3H), 2.53 (bs, 2H), 1.60 (m,1H), 1.32 (m, 3H), 1.02-1.13 (m, 2H), 1.10 (d, 2H).

[2198]¹³C-nmr (CDCl₃+2 drops of CD₃OD): δ=174.1, 166.4, 166.2, 163.1,163.0, 141.3, 113.8, 113.7, 113.5, 103.5, 55.2, 56.3, 43.0, 40.9, 32.2,28.1, 24.0, 18.2.

[2199] C₂₁H₂₆F₅N₃O₆ (MW=511.4); mass spectroscopy (MH⁺) 512.

EXAMPLE 217 Synthesis ofN′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-glutamide

[2200] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-glutamide hydrochloride (Bachem), the title compound was prepared as asolid (mp 260-263° C.). The reaction was monitored by tlc (Rf=0.77 in10% MeOH/DCM) and the product was purified by silica gel chromatography.

[2201] NMR data was as follows:

[2202]¹H nmr (CDCl₃): δ=8.40 (d, J=7.1 Hz, 1H), 8.02 (d, J=6.9, 1H), 7.2(m, 2H), 7.0 (m, 4H), 6.76 (s, 1H), 4.2 (m, 1H), 3.56 (s, 2H), 2.1 (m,2H), 1.9 (m, 2H), 1.21 (d, J=7.0 Hz, 3H).

[2203]¹³C-nmr (CDCl₃): δ=173.5, 172.4, 169.5, 112.5, 110.4, 102.3, 52.5,49.0, 41.6, 35.7, 31.8, 28.1, 18.4.

[2204] C₁₆H₂₀F₂N₄O₄ (MW=370); mass spectroscopy (MH⁺) 371.

EXAMPLE 218 Synthesis of Methyl1-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylate

[2205] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl pipecolinate hydrochloride (Aldrich), the title compound wasprepared as a solid (mp=114-118° C.). The reaction was monitored by tlc(Rf=0.71 in 10% MeOH/DCM) and the product was purified by acid/basewashes.

[2206] NMR data was as follows:

[2207]¹H nmr (CDCl₃): δ=6.95 (dd, J=7.1, 7.1, 7.1 Hz; 1H), 6.81 (d,J=6.1 Hz, 2H), 6.7 (m, 1H), 5.28 (dd, J=5.0 Hz, 12.6, 5.4, 1H), 4.93 (q,J=7.0, 6.9, 7.0 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 3H), 3.50 (s, 2H), 3.2(m, 1H), 2.27 (d, J=3.5 Hz, 1H), 1.5 (m, 5H), 1.31 (d, J=5.2 Hz, 3H).

[2208]¹³C-nmr (CDCl₃): δ=172.8; 172.6; 171.7; 171.6; 169.2; 169.1;112.9; 112.8; 112.7; 112.6; 103.2; 102.8; 53.0; 52.9; 52.9; 52.7; 46.2;46.1; 43.9; 43.9; 27.1; 26.8; 25.6; 21.4; 19.9; 18.5.

[2209] C₁₈H₂₂F₂N₂O₄ (MW=368); mass spectroscopy (MH⁺) 369.

EXAMPLE 219 Synthesis ofN-[(S)-3-Hydroxy-6methylhept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2210] Following General Procedure AA and usingN-[(S)-6-methyl-3-oxohept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(from Example 168 above), the title compound was prepared as a solid.The reaction was monitored by tlc (Rf=0.75 in 9:1 CHCl₃/ MeOH) and theproduct was purified by silica gel chromatography using 99:1 CHCl/MeOHas the eluent.

[2211] NMR data was as follows:

[2212]¹H nmr (CDCl₃): δ=6.81 (m, 1H), 6.72 (m, 2H), 6.39 (m, 2H), 4.45(m, 1H), 3.97 (m, 1H), 3.60 (m, 1H), 3.52 (s, 2H), 1.54 (m, 1H), 1.4 (m,5H), 1.09 (m, 3H), 0.9 (m, 6H).

[2213] Optical Rotation: [α]₂₃=−39° (c 1, MeOH).

[2214] C₁₉H₂₈F₂N₂O₃ (MW=448); mass spectroscopy (MH⁺) 449.

EXAMPLE 220 Synthesis ofN-[(S)-2-Hydroxy-1-phenyleth-1-yl]-N′-(3,5-Difluorophenylacetyl)-L-alaninamide

[2215] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(S)-2-hydroxy-1-phenyleth-1-ylamnine (e.g., (S)-phenylglycinol)(Aldrich), the title compound was prepared as a solid (mp=204-206° C.).The reaction was monitored by tlc (Rf=0.5 in 10% MeOH/CHCl₃) and theproduct was purified by silica gel chromatography using 5% MeOH/CHCl₃ asthe eluent, followed by recrystallization from acetonitrile.

[2216] NMR data was as follows:

[2217]¹H-nmr (DMSO-d₆): δ=1.24 (d, 3H), 4.38 (m, 1H), 4.80 (m, 2H).

[2218] Optical Rotation: [α]₂₀=+3.56°@589 nm (c 1.10, DMSO).

[2219] C₁₉H₂₀F₂N₂O₃ (MW=362.38); mass spectroscopy (MH⁺) 363.

EXAMPLE 221 Synthesis ofN-[N-(3,5-Difluorophenyl-α-fluoroacetyl)-L-alaniny]-L-phenylglycinetert-Butyl Ester

[2220] Following General Procedure M and using3,5-difluorophenyl-α-fluoroacetic acid (from Example D1 above) andN-(L-alaniny)-L-phenylglycine tert-butyl ester (prepared usingN-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl esterhydrochloride (Bachem) using General Procedure C, followed by removal ofthe BOC group using General Procedure P), the title compound wasprepared as a clear oil. The reaction was monitored by tlc (Rf=0.44 and0.51 in 1:1 EtOAc/hexanes) and the product was purified by LC 2000chromatography using 20% EtOAc/hexanes as the eluent.

[2221] NMR data was as follows:

[2222]¹H nmr (CDCl₃)(1:1 mixture of diasteromers): δ=1.37 (s, 9H), 1.39(s, 9H), 1.42 (d, J=7.0 Hz, 3H), 1.48 (d, J=7.0 Hz, 3H), 3.80 (d, J=7.0Hz, 1H), 4.62 (pent, J=7.0 Hz, 2H), 5.36 (d, J=7.1 Hz, 1H), 5.42 (d,J=7.2 Hz, 1H), 5.60 (d, J=4.7 Hz, 1H), 5.73 (d, J=4.7 Hz, 1H), 6.80 (m,2H), 6.97 (m, 4H), 7.20-7.33 (m, 12H).

[2223] C₂₃H₂₅F₃N₂O₄ (MW=450.2); mass spectroscopy (MH⁺) 451.

EXAMPLE 222 Synthesis ofN-[(S)-α-Hydroxy-α′-phenylisopropyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2224] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(S)-α-hydroxy-α′-phenylisopropylamine (e.g., L-phenylalaninol)(Aldrich), the title compound was prepared as a solid. The reaction wasmonitored by tlc (Rf=0.5 in 9:1 CHCl₃/MeOH) and the product was purifiedby silica gel chromatography using 95:5 CHCl₃/MeOH as the eluent.

[2225] NMR data was as follows: ¹H-nmr (CDCl₃): δ=7.33-7.17 (m, 5H),6.72 (m, 3H), 6.62 (d, 1H), 6.32 (d, 1H), 4.43 (m, 1H), 4.10 (m, 1H),3.61 (m, 2H), 3.45 (s, 2H), 2.84 (m, 2H), 1.32 (d, 3H).

[2226] Optical Rotation: [α]₂₃=−60° (c 1, MeOH).

[2227] C₂₀H₂₂F₂N₂O₃ (MW=376); mass spectroscopy (MH⁺) 377.

EXAMPLE 223 Synthesis ofN-[(lS,2R)-1-Hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2228] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(1S,2R)-1-hydroxy-1-phenylprop2-ylamine hydrochloride (e.g.,(1S,2R)-norephedrine hydrochloride) (Aldrich), the title compound wasprepared as a solid. The reaction was monitored by tlc (Rf=0.5 in 9:1CHCl₃/MeOH) and the product was purified by silica gel chromatographyusing 98:2 CHCl₃/ MeOH as the eluent.

[2229] NMR data was as follows:

[2230]¹H-nmr (CDCl₃): δ=7.31 (m, 5H), 6.84-6.64 (m, 4H), 4.86 (m, 1H),4.51 (m, 1H), 4.23 (m, 1H), 3.52 (s, 2H), 1.38 (d, 3H), 0.97 (d, 3H).

[2231] Optical Rotation: [α]₂₃=44 (c 1, MeOH).

[2232] C₂₀H₂₂F₂N₂O₃ (MW=376); mass spectroscopy (MH⁺) 377.

EXAMPLE 224 Synthesis ofN-2-Methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycinamide

[2233] Following General Procedure K and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester (fromExample 28 above) and 2-methoxyethylamine (Aldrich), the title compoundwas prepared as a solid (mp=148-151° C.). The reaction was monitored bytlc (Rf=0.53 in 10% MeOH/DCM +1 % TEA) and the product was purified bysilica gel chromatography.

[2234] NMR data was as follows:

[2235]¹H-nmr (CDCl₃): δ=8.2 (m, 1H), 7.1 (m, 1H), 6.6 (m, 8H0, 4.7 (m,1H), 4.0 (m, 1H), 3.6 (m, 2H), 3.39 (s, 2H), 3.2 (m, 4H), 3.1 (s, 3H),1.17 (d, J=7.2 Hz, 3H).

[2236]¹³C-nmr (CDCl₃): δ=176.3, 173.4, 172.2, 166.5, 163.4, 150.4,141.6, 114.1, 114.0, 113.9, 113.8, 103.9, 103.5, 72.2, 72.1, 59.4, 51.9,44.0, 43.0, 40.7, 17.9.

[2237] C₁₆H₂₁F₂N₃O₄ (MW=357); mass spectroscopy (MH⁺) 358.

EXAMPLE 225 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycineMethyl Ester

[2238] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and N-[2-(S)-aminocyclohexylacetyl]-L-phenylglycinemethyl ester hydrochloride (prepared from N-BOC-L-cyclohexylglycine(Sigma) and L-phenylglycine methyl ester hydrochloride (Aldrich) usingGeneral Procedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=234.4° C.).The reaction was monitored by tlc (Rf=0.65 in 5:95 MeOH/DCM) and theproduct was purified by recrystallization from ethyl acetate.

[2239] NMR data was as follows:

[2240]¹H-nmr (DMSO-d₃): δ=8.85 (d, J=6.5 Hz, 1H), 8.21 (d, J=8.9 Hz,1H), 7.37 (s, 5H), 7.07 (m, 1H), 6.97 (d, 2H), 5.36 (d, J=6.4 Hz, 1H),4.35 (t, J=7.7 Hz, 1H), 3.53 (m, SH), 1.65 (m, 6H), 1.06 (m, 5H).

[2241]¹³C-nmr (DMSOd₃): δ=171.065, 170.865, 168.953, 164.179, 163.967,160.282, 160.070, 141.210, 141.058, 135.766, 128.657, 128.374, 128.004,112.371, 112.238, 112.115, 111.981, 102.217, 101.808, 101.399, 56.568,56.471, 41.467, 40.354, 28.884, 28.025, 25.926, 25.669.

[2242] C₂₅H₂₈N₂O₄F₂ (MW=458.51); mass spectroscopy (MH⁺) 458.1.

EXAMPLE 226 Synthesis ofN-[(IR,2S)-1-Hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2243] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(IR,2S)-1-hydroxy-1-phenylprop2-ylamine hydrochloride (e.g.,(1R,2S)-norephedrine hydrochloride) (Aldrich), the title compound wasprepared as a foam. The reaction was monitored by tlc (Rf=0.5 in 9:1CHCl₃/MeOH).

[2244] NMR data was as follows:

[2245]¹H nmr (CDCl₃): δ=7.35 (m, 5H), 7.75 (m, 3H), 6.57 (d, 1H), 4.47(d, 1H), 4.26 (m, 1H), 3.48 (s, 2H), 1.32 (d, 3H), 1.01 (d, 3H).

[2246] Optical Rotation: [60 ]₂₃=−64° (c 1, MeOH).

[2247] C₂₀H₂₂F₂N₂O₃ (MW=376); mass spectroscopy (MH⁺) 377.

EXAMPLE 227 Synthesis ofN-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2248] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(1R,2S)-2-amino-1,2diphenylethanol (Aldrich), the title compound wasprepared as a solid (mp=217-219° C.). The reaction was monitored by tlc(Rf=0.4 in 10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 7% MeOH/CHCl₃ as the eluent, followed byrecrystallization from acetonitrile.

[2249] NMR data was as follows:

[2250]¹H nmr (DMSO-d₆): δ=0.76 (d, 3H), 5.43 (d, 1H).

[2251] Optical Rotation: [α]₂₀=−6.9°@589 nm (c 1.10, DMSO).

[2252] C₂₅H₂₄F₂N₂O₃ (MW=438.48); mass spectroscopy (MH⁺) 439.

EXAMPLE 228 Synthesis ofN-[(S)-1-Hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2253] Following General Procedure S and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate (fromExample 1 above), the title compound was prepared as a solid(mp=157-158.5° C.). The reaction was monitored by tlc (Rf=0.62 in 10%CH₃OH/CH₂Cl₂).

[2254] NMR data was as follows:

[2255]¹H nmr (CD₃OD): δ=5.9 (m, 2H), 5.8 (m, 1H), 4.37 (q, 1H), 3.8 (m,1H), 3.58 (s, 2H), 3.5 (m, 2H), 1.4 (m, 9H), 0.9 (m, 3H).

[2256]¹³C-nmr (CD₃OD): δ=175.4, 172.9, 166.7, 166.5, 163.5, 163.2,141.8, 141.7, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 65.6,53.2, 51.2, 43.3, 32.3, 29.7, 24.1, 18.7, 14.9.

[2257] C₁₇H₂₄F₂N₂O₃ (MW=342.39); mass spectroscopy (MH⁺) 343.

EXAMPLE 229 Synthesis ofN-[α-Hydroxy-α′-(4-hydroxyphenyl)isopropyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2258] Following General Procedure S and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester(from Example 15 above), the title compound was prepared as a solid(mp=179-183° C.). The reaction was monitored by tlc (Rf=0.42 in 10%MeOH/DCM) and the product was purified by recrystallization fromMeOH/diethyl ether.

[2259] NMR data was as follows:

[2260]¹H nmr (CDCl₃): δ=6.82 (d, J=8.3 Hz, 2H), 6.7 (m, 2H), 6.62 (t,J=9.1, 9.1 Hz, 1H), 6.47 (d, J=8.5 Hz, 2H), 4.1 (m, 1H), 3.7 (m, 1H),3.34 (s, 2H), 3.2 (m, 2H), 2.5 (m, 2H),- 1.08-0.94 (dd, J=7.1, 36.0, 7.1Hz, 3H).

[2261]¹³C-nmr (CDCl₃): δ=175.0, 172.8, 157.4, 131.8, 131.8, 130.7,116.6, 116.5, 113.9, 113.5, 64.1, 54.9, 51.1, 43.3, 37.4, 18.6.

[2262] C₂₀H₂₂F₂N₂O₄ (MW=392); mass spectroscopy (MH⁺)=393.

EXAMPLE 230 Synthesis ofN-2-Pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylaianinamide

[2263] Following General Procedure K and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester(from Example 94 above) and 2-(aminomethyl)pyridine (Aldrich), the titlecompound was prepared.

[2264] NMR data was as follows:

[2265]¹H nmr (CD₃OD): δ=8.45 (d, 1H), 7.75 (t, 1H), 7.2-7.4 (m, 6H), 7.1(d, 1H), 6.8-7.0 (m, 3H) 4.63 (t, 1H) 4.45 (s, 2H), 4.2-4.35 (m, 1H),3.6 (s, 2H), 3.6 (s, 2H), 3.0-3.25 (m, 2H), 1.30 (d, 3H)

[2266] 13C-nmr (CD₃OD): δ=175.4, 174.0, 173.3, 166.6, 163.3, 163.2,159.5, 150.0, 141.4, 139.4, 138.9, 130.9, 130.1, 128.4, 124.2, 123.2,114.0, 113.9, 113.7, 113.6, 103.9, 103.2, 56.9, 51.4, 45.8, 43.1, 39.0,18.2

[2267] C₂₆H₂₆F₂N₄O₃ (MW=480.52); mass spectroscopy (MH⁺)=481.

EXAMPLE 231 Synthesis ofN-[α-Hydroxy-α′-pyrid-2-ylisopropyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2268] Following General Procedure S and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate(from Example 19 above), the title compound was prepared as a solid(mp=225-229° C.). The reaction was monitored by tlc (Rf=0.66 in 10%MeOH/DCM) and the product was purified by recrystallization fromMeOH/diethyl ether.

[2269] NMR data was as follows:

[2270]¹H nmr (CDCl₃): δ=8.21 (d, J=4.5 Hz, 1H), 7.46 (t, J=6.3, 7.6 Hz,1H), 7.11 (d, J=7.6 Hz, 1H), 7.01 (t, J=5.5, 7.1 Hz, 1H), 6.70 (d, J=6.3Hz, 2H), 6.62 (t, J=9.6, 9.0 Hz, 1H), 4.1 (m, 1H), 3.4 (m, 1H), 3.33 (s,2H), 3.3 (m, 2H), 1.06 (d, J=7.0 Hz, 3H).

[2271]¹³C-nmr (CDCl₃): δ=172.754, 160.222, 150.134, 139.137, 126.198,123.680, 113.936, 113.602, 103.578, 64.854, 53.689, 51.191, 43.304,40.394, 18.769.

[2272] C₁₉H₂₁F₂N₃O₃ (MW=377); mass spectroscopy (MH⁺) 378.

EXAMPLE 232 Synthesis ofN-[α-Hydroxy-α′-pyrid-4ylisopropyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2273] Following General Procedure S and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate(from Example 23 above), the title compound was prepared as a solid(mp=189- 193° C.). The reaction was monitored by tlc (Rf=0.47 in 10%MeOH/DCM) and the product was purified by silica gel chromatography.

[2274] NMR data was as follows:

[2275]¹H nmr (CDCl₃): δ=8.18 (d, J=5.6 Hz, 2H), 7.27 (d, J=5.6 Hz, 2H),6.7 (m, 2H), 6.6 (m, 1H), 4.0 (m, 1H), 3.9 (m, 1H), 3.32 (s, 2H), 3.10(s, 2H), 2.9 (m, 2H), 1.07 (d, J=7.2, 3H).

[2276]¹³C-nmr (CDCl₃): δ=175.8, 150.4, 150.2, 126.8, 113.9, 113.6,103.6, 103.5, 72.0, 59.3, 55.2, 51.6, 42.9, 40.8, 38.3, 17.9.

[2277] C₁₉H₂₁F₂N₃O₃ (MW=377); mass spectroscopy (MH⁺) 378.

EXAMPLE 233 Synthesis ofN-[(S)-1-Hydroxy-4-methylpent-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2278] Isomer A:

[2279] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(S)-1-hydroxy-4-methylpent-2-ylamine (Oeucinol) (Bachem), the titlecompound was prepared as a solid (mp=141-151° C.). The reaction wasmonitored by tlc (Rf=0.5 in 5% MeOH/methylene chloride) and the productwas purified by recrystallization from EtOAc/hexanes.

[2280] NMR data was as follows:

[2281]¹H nmr (CD₃OD): δ=8.15 (s 1H), 7.5 (t, J=8 Hz, 1H), 6.80-6.55 (m,3H), 4.15 (m, J=3.5 Hz, 1H), 3.7 (m 1H), 3.35 (s 2H), 3.22 (t, J=3 Hz,2H), 1.4 (m, 1H), 1.1 (m, 5H), 0.7 (m, 6H).

[2282]¹³C-nmr (CD₃OD): δ=175.4, 175.3, 173.0, 113.9, 113.9, 113.6,113.5, 103.9, 103.6, 103.2, 66.1, 51.6, 51.4, 51.3, 51.3, 43.4, 41.7,41.6, 26.5, 26.3, 24.3, 22.8, 22.7, 19.0, 18.7, 18.6.

[2283] C₁₇H₂₄N₂O₃F₂ (MW=342.19); mass spectroscopy (MH⁺) 343.

[2284] Isomer B:

[2285] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(S)-1-hydroxy-4-methylpent-2-ylamine (1eucinol) (Aldrich), the titlecompound was prepared as a solid (mp=151-153° C.). The reaction wasmonitored by tlc (Rf=0.8 in 10% MeOH/DCM) and the product was purifiedby recrystallization, followed by flash column chromatography, followedby a preparative tlc using 10% MeOH/DCM as the eluent.

[2286] NMR data was as follows:

[2287]¹H nmr (CD₃OD): δ=8.15 (s 1H), 7.5 (t, J=8 Hz, 1H), 6.80-6.55 (m,3H), 4.15 (m, J=3.5 Hz, 1H), 3.7 (m, 1H), 3.35 (s, 2H), 3.22 (t, J=3 Hz,2H), 1.4 (m, 1H), I.l(m, 5H), 0.7 (m, 6H).

[2288]¹³C-nmr (CD₃OD): δ=175.2, 172.9, 166.6, 166.5, 141.7, 113.9,113.9, 113.8, 113.6, 113.6, 103.9, 103.6, 103.2, 66.1, 51.2, 50.4, 50.1,50.0, 49.8, 49.7, 49.6, 49.4, 49.38, 49.3, 49.0, 48.7, 43.4, 43.3, 41.7,26.3, 24.3, 22.8, 18.7.

[2289] C₁₇H₂₄N₂O₃F₂ (MW=342.19); mass spectroscopy (MH⁺) 342.

EXAMPLE 234 Synthesis ofN-[1-Methoxyprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2290] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and2-amino-1-methoxypropane (Aldrich), the title compound was prepared as asolid (mp=152° C.). The reaction was monitored by tlc (Rf=0.45 in 5%MeOH/DCM) and the product was purified by recrystallization frommethanol/water.

[2291] NMR data was as follows:

[2292]¹H nmr (CDCl₃): δ=6.9-6.7 (m, 3H), 6.6 (d, J=7 Hz, 1H), 6.3 (m,1H), 4.5 (m, J=7 Hz, 1H), 4.1 (m, 1H), 3.5 (s, 2H), 3.3 (m, 5H), 1.4 (d,J=7 Hz, 3H), 1.15 (t, J=8 Hz, 3H).

[2293]¹³C-nmr (CDCl₃): δ=172.0, 113.0, 112.9, 112.62, 112.60, 103.7,103.4, 78.0, 77.6, 77.2, 75.8, 75.7, 59.6, 59.58, 49.6, 49.5, 45.6,45.6, 43.4, 19.4, 19.38, 18.9, 18.0.

[2294] C₁₇H₂₀N₂O₃F₂ (MW=314.14); mass spectroscopy (MH⁺) 315.

EXAMPLE 235 Synthesis ofN-[1-Hydroxy-3-methylbut-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2295] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andvalinol (Bachem), the title compound was prepared as a solid (mp176-179° C.). The reaction was monitored by tlc (Rf=0.4 in 5% MeOH/DCM)and the product was purified by recrystallization from EtOAc/hexanes.

[2296] NMR data was as follows:

[2297]¹H nmr (CD₃OD): δ=7.5 (d, J=9 Hz, 1H), 6.8-6.5 (m, 3H), 4.15 (m,1H), 3.45 (m, 2H), 3.35 (m, 3H), 1.65 (m, J=7 Hz, 1H), 1.20 (d, J=5 Hz,3H), 0.7 (m, 6H).

[2298]¹³C-nmr (acetone-d₆): δ=113.7, 113.4, 103.0, 63.3, 57.7, 57.69,50.5, 50.4, 43.2, 31.1, 30.8, 30.6, 30.5, 30.3, 30.2, 30.1, 29.9, 29.9,29.8, 29.7, 29.6, 20.5, 20.4, 19.5, 19.1, 19.0, 18.8.

[2299] C₁₆H₂₂N₂O₃F₂ (MW=329.19); mass spectroscopy (MH⁺) 329.

EXAMPLE 236 Synthesis of MethylN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6aminopyrid-2-yl)acetate

[2300] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino-2-(6-aminopyrid-2-yl)acetate (prepared from2-(methoxyimino)-2-(6-aminopyrid-2-yl)acetic acid [CAS 71470-33-2] usingGeneral Procedures G and AC above), the title compound was prepared. Theproduct was purified by LC 2000 preparative column chromatography using1:1 EtOAc/hexanes as the eluent.

[2301] NMR data was as follows:

[2302]¹H nmr (CDCl₃): δ=7.65-6.5 (m, 6H), 6.4 (d, J=8.19 Hz, 1H),5.49-5.33 (m, 1H), 4.8-4.5 (m, 2H), 3.7 (s, 3H), 3.6 (s, 1H), 3.5 (s,1H), 2.06 (bs, 2H), 1.44 (d, J=7.06 Hz, 1.5 H), 1.35 (d, 7.06 Hz, 1.5H).

[2303] C₁₉H₂₀N₄O₄F₂ (MW=406.39); mass spectroscopy (MH⁺) 406.3.

EXAMPLE 237 Synthesis ofN-[1-Hydroxyprop2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2304] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andalanol (Bachem), the title compound was prepared as a solid (mp=158-163°C.). The reaction was monitored by tic (Rf=0.7 in 10% MeOH/DCM) and theproduct was purified by recrystallization from ethyl acetate, followedby flash column chromatography using 10% MeOH/DCM.

[2305] NMR data was as follows:

[2306]¹H nmr (CD₃OD): δ=8.2 (m, 1H), 7.6 (m, 1H), 4.1 (m, J=7 Hz, 1H),3.7 (m, J=5 Hz, 1H), 3.35 (s, 2H), 3.25 (m, 2H), 1.15 (d, J=7 Hz, 3H),0;9 (d, J=7 Hz, 3H).

[2307]¹³C-nmr (CD₃OD): δ=175.1, 175.06, 172.9, 166.6, 166.5, 163.4,163.2, 141.6, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6, 103.2, 66.5,51.4, 51.3, 51.3, 51.2, 50.4, 50.1, 49.8, 49.77, 49.6, 49.5, 49.3, 49.1,49.0, 48.7, 43.3, 18.8, 17.5.

[2308] C₁₄H₁₈N₂O₃F₂ (MW 300); mass spectroscopy (MH⁺) 301.

EXAMPLE 238 Synthesis ofN-[(S)-2-methoxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2309] Following General Procedure C and using 3,5-difluorophenylaceticacid (Oakwood) and N-[(S)-2-methoxy-1-phenyleth-1-yl]-L-alaninamide(prepared from N-BOC-L-alanine (Sigma) and (S)-phenylglycinol methylether (from Example D 15 above) using General Procedure C, followed byremoval of the BOC-group using General Procedure P), the title compoundwas prepared as a solid (mp=180-182° C.). The reaction was monitored bytlc (Rf=0.4 in 10% MeOH/CHCl₃) and the product was purified by silicagel chromatography using 5% MeOH/CHCl₃ as the eluent, followed byrecrystallization from 1- chlorobutane/acetonitrile.

[2310] NMR data was as follows:

[2311]¹H nmr (DMSO-d₆): δ=1.22 (d, 3H), 3.23 (s, 3H).

[2312] Optical Rotation: [α]₂₀=+12.3°@589 nm (c 1.04, DMSO).

[2313] C₂₀H₂₂F₂N₂O₃ (MW=376.41); mass spectroscopy (MH⁺) 377.

EXAMPLE 239 Synthesis ofN-[(S)-1-Methoxy-2-phenylpro-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2314] Following General Procedure B and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Exanple B2 above) andL-phenylalaninol methyl ether hydrochloride (Fluka), the title compoundwas prepared as a fluffy solid. The product was purified byrecrystallization from MeOH/EtOAc.

[2315] NMR data was as follows:

[2316]¹H nmr (CDCl₃): δ=1.31 (d, J=7 Hz, 3H), 2.8 (d, J=7 Hz, 2H), 3.28(d, J=3 Hz, 2H), 3.32 (s, 3H), 3.47 (s, 2H), 4.15-4.3 (m, 1H), 4.35-4.5(m, 1H), 6.3-6.5 (m, 2H), 6.6-6.9 (m, 3H), 7.1-7.35 (m, 5H).

[2317]¹³C-nmr (CDCl₃): δ=19.1, 37.8, 43.4, 49.6, 51.0, 59.6, 72.7,103.4, 112.6, 113.0, 127.1, 129.0, 129.9, 138.3, 169.8, 172.1.

EXAMPLE 240 Synthesis ofN-[(S)-1-Acetoxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2318] Following General Procedure V and usingN-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(from Example 228 above), the title compound was prepared as a solid(mp=144-145° C.). The reaction was monitored by tlc (Rf=0.42 in 10%CH₃OH/CH₂Cl₂).

[2319] NMR data was as follows:

[2320]¹H nmr (CD₃OD): δ=6.7 (m, 2H), 6.6 (m, 1H), 4.09 (q, 1H), 3.9-3.7(m, 3H), 3.35 (s, 2H), 1.79 (s, 3H), 1.4-1.0 (m, 9H), 0.6 (m, 3H).

[2321]¹³C-nmr (CD₃OD): δ=175.5, 173.2, 172.8, 166.6, 166.5, 163.4,163.2, 141.8, 141.7, 141.5, 113.9, 113.8, 113.7, 113.6, 103.9, 103.5,103.2, 67.5, 51.2, 43.28, 43.26, 32.2, 29.6, 24.0, 21.3, 18.8, 14.8.

[2322] C₁₉H₂₆F₂N₂O₄ (MW=384.43); mass spectroscopy (MH⁺) 385.

EXAMPLE 241 Synthesis ofN-[(S)-1-(tert-Butylcarbonyloxy)-hex-2-yl]-N′-(3,5difluorophenylacetyl)-L-alaninamide

[2323] Following General Procedure W and usingN-[(S)-1-hydroxyhex-2-yl]-N′-(3,5difluorophenylacetyl)-L-alaninamide(from Example 228 above) and trimethylacetyl chloride (Aldrich), thetitle compound was prepared as a solid (mp=104-107.5° C.). The reactionwas monitored by tlc (Rf=0.43 in 10% CH₃OH/CH₂Cl₂) and the product waspurified by preparative thin layer chromatography using 10% CH₃OH/CH₂Cl₂as the eluent.

[2324] NMR data was as follows:

[2325]¹H nmr (CD₃OD): δ=7.67 (bd, 1H), 6.7 (m, 2H), 6.6 (m, 1H), 4.14(q, 1H), 3.9-3.6 (m, 3H), 3.35 (s, 2H), 1.4-1.0 (m, 9H), 0.98 (s, 9H),0.6 (m, 3H).

[2326]¹³C-nmr (CD₃OD): δ=180.3, 175.3, 175.2, 172.8, 166.6, 166.5,163.4, 163.2, 141.8, 141.7, 141.5, 133.9, 113.8, 113.7, 113.6, 103.9,103.6, 103.2, 67.6, 51.1, 51.0, 43.3, 40.4, 32.4, 32.3, 29.5, 28.2,24.0, 19.0, 14.9.

[2327] C₂₂H₃₂F₂N₂O₄ (MW 426.51); mass spectroscopy (MH⁺) 427.5.

EXAMPLE 242 Synthesis ofN-[2-Hydroxy-1-(thien-2-yl)ethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2328] Following General Procedure S and using methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate(from Example 178 above), the title compound was prepared as a solid(mp=201-202° C.). The product was purified by trituration using 1:1hexanes/EtOAc.

[2329] NMR data was as follows:

[2330]¹H nmr (DMSO-d₆): δ=8.4-8.25 (m, 2H), 7.4-7.35 (m, 2H), 7.3-6.91(m, 4H), 5.1-4.85 (m, 1H), 4.4-4.3 (m, 1H), 3.7-3.5 (m, 2H), 3.51 (s,1H), 3.50 (s, 1H), 1.23-1.19 (overlaying doublets, 3H).

[2331] C₂₁H₂₃F₂N₂O₃ (MW=368.4); mass spectroscopy (MH⁺) 368.

EXAMPLE 243 Synthesis ofN-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N′-(3,5difluorophenylacetyl)-L-alaninamide

[2332] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and(S)-2-hydroxy-2-methyl-1-phenylprop-1-ylamine (from EXAMPLE D16 above),the title compound was prepared as a solid. The product was purified byrecrystallization from methanol/ethyl acetate.

[2333] NMR data was as follows:

[2334]¹H nmr (DMSO-d₆): δ=8.32 (d, 1H), 8.11 (d, 1H), 7.20-7.33 (m, 5H),7.08 (m, 1H), 6.96 (m, 2H), 4.68 (d, 1H), 4.53 (s, 1H), 4.95 (m,1H),3.50 (d, 2H), 1.25 (d, 3H), 1.08 (s, 3H), 0.98 (s, 3H).

[2335] Optical Rotation: [α]₂₃=−11° (c 1, MeOH).

[2336] C₂₁H₂₄F₂N₂O₃ (MW=390.42); mass spectroscopy (MH⁺) 391.

[2337] Example 244

Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L(thien-2-yl)glycinyl]-L-phenylalaninetert-Butyl Ester

[2338] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-(2-thienyl)glycinyl--L-phenylglycine tert-butylester (prepared using N-(9-florenylmethoxycarbonyl)-L-(2-thienyl)glycine(prepared as described below) and L-phenylglycine tert-butyl esterhydrochloride using General Procedure AH, followed by deprotection usingdicyclohexylamine in DMF and THF), the title compound was prepared as asolid (mp=176-177° C.). The product was purified by flash chromatographyusing EtOAc/dichloromethane as the eluent.

[2339] C₂₆H₂₆N₂O₄F₂ (MW=500.56); mass spectroscopy (MH⁺) 500.

Preparation of N-(9-Fluorenylmethoxycarbonyl)-L-(2-Thienyl)glycine

[2340] A round bottom flask containing a magnetic stir bar under anatmosphere of nitrogen at room temperature was charged with water,dioxane, sodium carbonate (2.5 eq.) and L-α-(2-thienyl)glycine (1.0 eq.)(Sigma). Stirring was initiated and the slurry was cooled in an icebath. 9-Flurenylmethyl chloroformate was added portionwise to thereaction and stirring was continued in an ice bath for 4 hours followedby 8 hours at room temperature. The reaction mixture was poured ontowater and extracted wilth diethyl ether. The aqueous layer was cooled inan ice bath and acidified with vigorous stirring to a pH of 2. Theresulting solid was isolated via vacuum filtration, washed with water(3×) and dried under reduced pressure.

EXAMPLE 245 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-Lphenylglycinyl]-L-phenylglycinol

[2341] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared fromN-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol (Novabiochem)using General Procedure AH, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=231.4° C.). The product was purified by crystallization from ethylacetate.

[2342] C₂₄H₂₂N₂O₃F₂ (MW=424.45); mass spectroscopy (MH⁺) 424.9.

EXAMPLE 246 Synthesis ofN-[N-(Cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinol

[2343] Following General Procedure E and using cyclopropaneacetic acid(Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared fromN-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol (Novabiochem)using General Procedure AH, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared as a solid(mp=202.5° C.). The product was purified by crystallization from ethylacetate.

[2344] C₂₁H₂₄N₂O₃ (MW=352.43); mass spectroscopy (MH⁺) 353.2.

EXAMPLE 247 Synthesis ofN-[N-(Cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinol

[2345] Following General Procedure E and using cyclopentaneacetic acid(Aldrich) and L-phenylglycinyl-L-phenylglycinol (prepared fromN-BOC-L-phenylgycine (Novabiochem) and L-phenylglycinol (Novabiochem)using General Procedure AH, followed by removal of the BOC-group usingGeneral Procedure P), the title compound was prepared-as a solid(mp=201.4° C.). The product was purified by flash chromatography usingMeOH/CH₂CH₂ as the eluent.

[2346] C₂₃H₂₈N₂O₃ (MW=380.49); mass spectroscopy (MH⁺) 381.4.

EXAMPLE 248 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide

[2347] Following General Procedure AO and usingN-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinemethyl ester (from Example 99 above), the title compound was prepared asa solid (mp=285.5-288.5° C.).

[2348] C₂₄H₂₁N₃O₃F₂ (MW=437.45); mass spectroscopy (MH⁺) 437.1.

EXAMPLE 249 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide

[2349] Following General Procedure AO and usingN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester(from Example 94 above), the title compound was prepared as a solid(mp=260.3-264.3° C.). The product was purified by recrystallization fromethyl acetate/methanol.

[2350] C₂₁H₂₃N₃O₃F₂ (MW=403.43); mass spectroscopy (MH⁺) 404.

EXAMPLE 250 Synthesis ofN-[N-(2-Thienylacetyl)-L-alaninyl]-L-phenylglycinamide

[2351] Following the General Procedures described herein, the titlecompound was prepared.

EXAMPLE 251 Synthesis ofN-[N-(n-Caproyl)-L-alaninyl]-L-phenylglycinamide

[2352] Following the General Procedures described herein, the titlecompound was prepared.

EXAMPLE 252 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine MethylEster

[2353] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-phenylglycinyl-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-norleucine (Lancaster) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=188-189.5°C.). The product was purified by flash chromatography using ethylacetate/hexanes as the eluant.

[2354] C₂₃H₂₆N₂O₄F₂ (MW=432.47); mass spectroscopy (MH⁺) 432.

EXAMPLE 253 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-noryalinyl]-L-phenylglycine MethylEster

[2355] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-norvalinyl-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-norvaline (Lancaster) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=204-205°C.). The product was purified by flash chromatography using ethylacetate/hexanes as the eluent.

[2356] C₂₂H₂₄N₂O₄F₂ (MW=418.44); mass spectroscopy (MH⁺) 418.3.

EXAMPLE 254 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine MethylEster

[2357] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-tert-leucinyl-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-tert-leucine (Bachem) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=176.4° C.).The product was purified by flash chromatography using ethylacetate/hexanes as the eluent.

[2358] C₂₃H₂₆N₂O₄F₂ (MW=432.47); mass spectroscopy (MH⁺) 432.0.

EXAMPLE 255 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine MethylEster

[2359] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-isoleucinyl-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-isoleucine (Aldrich) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=228.8° C.).The product was purified by flash chromatography using ethylacetate/hexanes as the eluent.

[2360] C₂₃H₂₆N₂O₄F₂ (MW=432.46); mass spectroscopy (MH⁺) 433.4.

EXAMPLE 256 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-cyclohexylaianinyl]-L-phenylglycineMethyl Ester

[2361] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-cyclohexylalaninyl-L-phenylglycine methyl esterhydrochloride (prepared from N-BOC-L-cyclohexylalanine (Sigma) andL-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=174.8° C.).The product was purified by flash chromatography using ethylacetate/hexanes as the eluent.

[2362] C₂₆H₃₀N₂O₄F₂ (MW=472.53); mass spectroscopy (MH⁺) 473.2.

EXAMPLE 257 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino2-(cyclopropyl)acetyl]-L-phenylglycineMethyl Ester

[2363] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and (S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycinemethyl ester hydrochloride (prepared fromN-BOC-(S)-2-amino-2-cyclopropylacetic acid (prepared fromcyclopropylacetic acid (Lancaster) and (4S)-4-benzyl-2-oxaxolidinone(Aldrich) using the procedures described in Evans et al., J. Am. Chem.Soc., 1990, 112, 4011-4030 and references cited therein) and L-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=225-226.5°C.). The product was purified by flash chromatography using MeOH/CHCl₃as the eluent.

[2364] C₂₂H₂₂N₂O₄F₂ (MW=416.42); mass spectroscopy (MH⁺) 417.3.

EXAMPLE 258 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino2(thien-3yl)acetyl]-L-phenylglycineMethyl Ester

[2365] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-(S)-²-amino-²-(thien-3-yl)acetyl-L-phenylglycinemethyl ester hydrochloride (prepared from N-BOC-L-thien-3-ylglycine(prepared from L-α-2-thienylglycine (Sigma) using General Procedure AJ)and L-phenylglycine methyl ester hydrochloride (Aldrich) using GeneralProcedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=229.3° C.).The product was purified by crystallization from ethyl acetate/hexanes.

[2366] C₂₃H₂₀N₂O₄SF₂ (MW=458.49); mass spectroscopy (MH⁺) 458.

EXAMPLE 259 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino2-(thien-2-yl)acetyl]-L-phenylglycineMethyl Ester

[2367] Following General Procedure AH and using 3,5-difluorophenylaceticacid (Aldrich) and L-(S)-²-amino-2-(thien-2-yl)acetyl-L-phenylglycinemethyl ester hydrochloride (prepared from N-BOC-L-thien-2-ylglycine(prepared from L-α-(thien-2-yl)glycine (Sigma) using General ProcedureAI) and L-phenylglycine methyl ester hydrochloride (Aldrich) usingGeneral Procedure E, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared as a solid (mp=230.8° C.).The product was purified by flash chromatographyl using MeOH/CH₂CH₂ asthe eluant.

[2368] C₂₃H₂₀N₂O₄F₂S(MW=458.49); mass spectroscopy (MH⁺) 458.

EXAMPLE 260 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L(4fluorophenyl)glycinyl]-L-phenylglycineMethyl Ester

[2369] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-(4-fluorophenyl)glycinyl-L-phenylglycine methylester hydrochloride (prepared from N-Cbz-(4-fluorophenyl)glycine(prepared from (4-fluorophenyl)glycine (prepared as described below)using General Procedure AK) and L-phenylglycine methyl esterhydrochloride (Aldrich) using General Procedure E, followed by silicagel chromatography using 5% ethyl acetate/toluene as the eluant andremoval of the Cbz-group using General Procedure AJ), the title compoundwas prepared as a solid (mp=213.1° C.). The product was purified byflash chromatography using ethyl acetate/CHCl₃ as the eluent.

[2370] C₂₅H₂₁N₂O₄F₂ (MW 470.44); mass spectroscopy (MH⁺) 470.1.

[2371] Preparation of (4-fluorophenyl)glycine:

[2372] (S)-(−)-4-Benzyl-2-oxazolidinone (15.0 g, 93 mmol) (Aldrich) wasdissolved in THF (100 mL). The solution was cooled to −70° C. andreaction flask was purged twice with nitrogen. n-Butyl lithium (44.6 mL,2.0M, 89 mmol) was added to form a solid precipitate which broke up onstirring wo afford a slurry. 4-Fluorophenylacetyl chloride 16.1 g, 93mmol) (Aldrich) was added to afford a light green solution and stirringwas continued for 45 minutes. The reaction mixture was then stirred atroom temperature for 1 hour. The reaction mixture was then treated withsaturated sodium bisulfate (100 mL) and ethyl acetate (100 mL). Theorganic phase was washed with water, followed by brine. The organicphase was then dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford an oil. The oil was crystallized toafford 24.4 g of1-(4-fluorophenylacetyl)-(S)-(-)⁴-Benzyl-2-oxazolidinone.

[2373] Potassium hexamethyldisilazane (140 mL, 0.5M, 70.0 mmol) wasadded to THF (80 mL). The solution was cooled to −50° C under nitrogenand a cold solution (−60° C.) of1-(4-fluorophenylacetyl)-(S)-(-)-4-benzyl-2-oxazolidinone (15.0 g, 46mmol) in THF (100 niL). The resulting mixture was allowed to stir at−70° C. for 1 hour and to warm to about −20° C. The mixture was recooled to −70° C. and a cold solution (−65° C.) of trasyl azide (21.6 g,70.0 mmol) was added. The mixture was allowed to stir for about15 min.while warming to −45° C. and then glacial acetic acid (18 mL) was added.The mixture was then stirred at about 30° C. for 3 hours. A precipitateformed and was removed by filtration. The filtrate was concentrated by50 and then washed with water, saturated sodium bicarbonate solution andbrine. The organic phase was dried over sodium sulfate, concentratedunder reduced pressure to afford 37.7 g of crude1-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(−)-4-benzyl-2-oxazolidinone.

[2374] Crude1-[2-(4-fluorophenyl)-2-azidoacetyl]-(S)-(−)-4-benzyl-2-oxazolidinone(10.0 g, 28.0 mmol) was dissolved in 100 mL of THF and 100 mL ofmethanol and trifluoroacetic acid (4.31 mL, 75.3 mmol) was added.Pallidium on carbon (10%, 2.0 g) was added and the mixture washydrogenated on a Paar shaker at 50 psi overnight at room temperature.The reaction mixture was then filtered through a plug of Celite and thesolid cake was rinsed with 100 mL of methanol. The filterate wasconcentrated to afford1-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(−)-4-benzyl-2-oxazolidinonetrifluoroacetate salt as a yellowish oil.

[2375] To a mixture of THF and de-ionized water (50 mL/50 mL) was added1-[2-(4-fluorophenyl)-2-aminoacetyl]-(S)-(−)-4-benzyl-2-oxazolidinonetrifluoroacetate salt (4.14 g, 9.7 mmol) and lithium hydroxidemonohydrate (1.22 g, 29 mmol). The homogenous solution was stirred for 2hours at room temperature at which time Tlc indicated completedisappearance of starting material. The mixture was extracted withdichloromethane (3×100 mL) and the aqueous phase was acidified to pH 2-3while cooling in an ice-bath. A precipitate formed. The mixture was thencooled in an ice-bath for 1.5 hours and then filtered. The solid waswashed with water followed by pentane to afford 4-fluorophenylglycinehydrochloride.

EXAMPLE 261 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-D(4-fluorophenyl)glycinyl]-L-phenylglycineMethyl Ester

[2376] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and D-(4-fluorophenyl)glycinyl-L-phenylglycine methylester hydrochloride (prepared from N-Cbz-(4-fluorophenyl)glycine(prepared from (4-fluorophenyl)glycine (prepared as in Example 260)using General Procedure AK) and L-phenylglycine methyl esterhydrochloride (Aldrich) using General Procedure E, followed by silicagel chromatography using 5% ethyl acetate/toluene as the eluant andremoval of the Cbz-group using General Procedure AJ), the title compoundwas prepared as a solid (mp=188.0° C.). The product was purified byflash chromatography using ethyl acetate/CHCl₃ as the eluent.

[2377] C₂₅H₂₁N₂O₄F₃ (MW=470.44); mass spectroscopy (MH⁺) 470.1.

EXAMPLE 262 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycineMethyl Ester

[2378] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-(4-methoxyphenyl)glycinyl-L-phenylglycine methylester hydrochloride (prepared from N-Cbz-L-(4-methoxyphenyl)glycine(prepared from (4-methoxyphenyl)glycine (prepared by the Bucherermodification of the Strecker procedure as described in Greenstein etal., “The Chemistry of Amino Acids”, Vol. 1, p. 698, Wiley, New York(1961)) using General Procedure AK) and L-phenylglycine methyl esterhydrochloride (Aldrich) using General Procedure E, followed by removalof the Cbz-group using General Procedure AJ), the title compound wasprepared as a solid (mp=224.6° C.). The product was purified by flashchromatography using MeOH/CHCl₃ as the eluent.

[2379] C₂₆H₂₄N₂O₅F₂ (MW=482.48); mass spectroscopy (MH⁺) 482.1.

EXAMPLE 263 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-phenylglycinetert-Butyl Ester

[2380] Following General Procedure E and using 3,5-difluorophenylaceticacid (Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl ester(prepared from N-Cbz-L-phenylglycine (Novabiochem) and L-phenylglycinetert-butyl ester hydrochloride (Novabiochem) using General Procedure AH,followed by removal of the Cbz-group using General Procedure AJ), thetitle compound was prepared as a solid (mp=185.0° C.). The product waspurified by flash chromatography using ethyl acetate/CH₂CH₂ as theeluant.

[2381] C₂₆H₂₈N₂O₄F₂ (MW 494.54); mass spectroscopy (MH+, minus CO₂-t-Bu)393.

EXAMPLE 264 Synthesis ofN-[N-(Cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-ButylEster

[2382] Following General Procedure E and using cyclopropylacetic acid(Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl esterhydrochloride (prepared from N-Cbz-L-phenylglycine (Novabiochem) andL-phenylglycine tert-butyl ester hydrochloride (Novabiochem) usingGeneral Procedure AH, followed by removal of the Cbz-group using GeneralProcedure AJ), the title compound was prepared as a solid (mp=187.5°C.). The product was purified by crystallization from ethyl acetate.

[2383] C₂₅H₃₀N₂O₄ (MW=422.53); mass spectroscopy (MH⁺) 423.4.

EXAMPLE 265 Synthesis ofN-[N-(Cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-ButylEster

[2384] Following General Procedure E and using cyclopropylacetic acid(Aldrich) and L-phenylglycinyl-L-phenylglycine tert-butyl esterhydrochloride (prepared from N-Cbz-L-phenylglycine (Novabiochem) andL-phenylglycine tert-butyl ester hydrochloride (Novabiochem) usingGeneral Procedure AH, followed by removal of the Cbz-group using GeneralProcedure AJ), the title compound was prepared as a solid (mp=190.8°C.). The product was purified by crystallization from ethyl acetate.

[2385] C₂₇H₃₄N₂O₄ (MW 450.58); mass spectroscopy (MH⁺) 451.

EXAMPLE 266 Synthesis ofN-[N-(t-Butylacetyl)-L-alaninyl]-L-phenylglycinamide

[2386] Following the General Procedures described herein, the titlecompound was prepared.

EXAMPLE 267 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L(5-bromothien-2-yl)glycinamide

[2387] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),5-bromo>2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=227-228° C.). The product was purified byrecrystallization from ethyl acetate/hexanes.

[2388] C₂₁H₂₄N₃O₃BrS (MW=515); mass spectroscopy (MH⁺) 515, 415.

EXAMPLE 268 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D(5bromothien-2-yI)glycinamide

[2389] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),5-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=216-217° C.). The product was purified byrecrystallization from ethyl acetate/hexanes.

[2390] C₂₁H₂₄N₃O₃BrS (MW=515); mass spectroscopy (MH⁺) 515, 415.

EXAMPLE 269 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L(4bromothien-2-yl)glycinamide

[2391] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),4-bromo-2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=246-247° C.). The product was purified byrecrystallization from ethyl acetate/hexanes.

[2392] C₂₁H₂₄N₃O₃BrS (MW=515); mass spectroscopy (MH⁺) 515, 415.

EXAMPLE 270 Synthesis ofN-tert-Butyl-N′-[N′-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)glycinamide

[2393] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=241-242° C.). The product was purified byrecrystallization from ethyl acetate/hexanes.

[2394] C₂₁H₂₅N₃O₃F₂S (MW=438); mass spectroscopy (MH⁺) 438, 338.

EXAMPLE 271 Synthesis of N-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D(thien-2-yl)glycinamnide

[2395] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),2-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=235-236° C.). The product was purified byrecrystallization from ethyl acetate/hexanes.

[2396] C₂₁H₂₅N₃O₃F₂S (MW=438); mass spectroscopy (MH⁺) 438, 338.

EXAMPLE 272 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L(thien-3-yl)glycinamide

[2397] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),3-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=240-241° C.). The product was purified byrecrystallization from ethyl acetate/hexanes.

[2398] C₂₁H₂₅N₃O₃F₂S (MW=438); mass spectroscopy (MH⁺) 438, 338.

EXAMPLE 273 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-(thien-3-yl)glycinamide

[2399] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),3-thiophenecarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=245-246° C.). The product was purified byrecrystallization from ethyl acetatelhexanes.

[2400] C₂₁H₂₅N₃O₃F₂S (MW=438); mass spectroscopy (MH⁺) 438, 338.

EXAMPLE 274 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide

[2401] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich) andtert-butylisocyanide (Aldrich), the title compound was prepared as asolid (mp=239-240° C.). The reaction was monitored by tlc (Rf=0.25 in50% ethyl acetateihexanes).

[2402] C₂₃H₂₇N₃O₃F₂ (MW=431.53); mass spectroscopy (MH⁺) 432.

EXAMPLE 275 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[2403] Following General Procedure AL and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich) andtert-butylisocyanide (Aldrich), the title compound was prepared as asolid (mp=240-241 C.).

[2404] C₂₃H₂₇N₃O₃F₂ (MW=431.53); mass spectroscopy (MH⁺) 432.

EXAMPLE 276 Synthesis of N-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothien-2-yl)glycinamide

[2405] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),5-chloro-2-thiophenecarboxaldehyde (from Example D17 above),(S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide(Aldrich), the title compound was prepared as a solid (mp=195-198° C.).The reaction was monitored by tlc (Rf=0.15 in 50% ethylacetate/hexanes).

[2406] C₂₁H₂₄N₃O₃F₂Cl (MW=472); mass spectroscopy (MH⁺) 472.

EXAMPLE 277 Synthesis ofN-Cyclohexyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L4-(phenyl)phenylglycinamide

[2407] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),4-biphenylcarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and cyclohexylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=300° C. (dec.)). The reaction was monitored bytlc (Rf=0.23 in 50% ethyl acetate/hexanes).

[2408] C₃₁H₃₃N₃O₃F₂ (MW=533.62); mass spectroscopy (MH⁺, minuscyclohexylamide) 408.2.

EXAMPLE 278 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L3-(phenoxy)phenylglycinamide

[2409] Following General Procedure AM and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),3-phenoxybenzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich)and tert-butylisocyanide (Aldrich), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.29 in 50% ethyl acetate/hexanes).

[2410] C₂₉H₃₁N₃O₄F₂ (MW=523.63); mass spectroscopy (MH⁺) 524.24.

EXAMPLE 279 Synthesis ofN-(S)-(−)-Methylbenzyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2411] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich) and(S)-(−)-α-methylbenzylisocyanide (from Example D18 above), the titlecompound was prepared.

[2412] C₂₇H₂₇N₃O₃F₂ (MW=479.53); mass spectroscopy (MH⁺) 480.21.

[2413] By following the procedures set forth above,N-(R)-(+)-α-Methylbenzyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamidewas prepared merely by substitution of the appropriate isomer.

[2414] C₂₇H₂₇N₃O₃F₂ (MW=479.53); mass spectroscopy (MH⁺) 480.1.

EXAMPLE 280 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L3-(phenyl)phenylglycinamide

[2415] Following General Procedure AM and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),3-phenylbenzaldehyde (from Example D20 above),(S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide(Aldrich), the title compound was prepared. The reaction was monitoredby tlc (Rf=0.25 in 50% ethyl acetate/hexanes).

[2416] C₂₉H₃₁N₃O₃F₂ (MW=507.63); mass spectroscopy (MH⁺) 508.2.

EXAMPLE 281 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenylglycinamide

[2417] Following General Procedure AM and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),4-ethylbenzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich) andtert-butylisocyanide (Aldrich), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.20 in 50% ethyl acetate/hexanes).

[2418] C₂₅H₃₁N₃O₃F₂ (MW=459.59); mass spectroscopy (MH⁺) 460.2.

EXAMPLE 282 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L2-(phenyl)phenylglycinarfide

[2419] Following General Procedure AM and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),2-phenylbenzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich)and tert-butylisocyanide (Aldrich), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.15 in 50% ethyl acetate/hexanes).

[2420] C₂₉H₃₁N₃O₃F₂ (MW=507.63); mass spectroscopy (MH⁺, minustert-butylamide) 409.

EXAMPLE 283 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L2-(benzyl)phenylglycinamide

[2421] Following General Procedure AM and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),2-(benzyl)benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine (Aldrich)and tert-butylisocyanide (Aldrich), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.19 in 50% ethyl acetate/hexanes).

[2422] C₃₀H₃₃N₃O₃F₂ (MW=521.66); mass spectroscopy (MH⁺) 522.26.

EXAMPLE 284 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamnide

[2423] Following General Procedure AM and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example 82 above),4-bromobenzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamnie (Aldrich) andtert-butylisocyanide (Aldrich), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.06 in 50% ethyl acetate/hexanes).

[2424] C₂₃H₂₆N₃O₃F₂ (MW=510.42); mass spectroscopy (MH⁺) 512.1.

EXAMPLE 285 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-4-(cyclohexyl)phenylglycinamide

[2425] Following General Procedure AL and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example 82 above),4-(cyclohexyl)benzaldehyde (from Example D21 above),(S)-(+)-α-methylbenzylamine (Aldrich) and tert-butylisocyanide(Aldrich), the title compound was prepared as a solid (mp=232-235° C.).

[2426] C₂₉H₃₇N₃O₃F₂ (MW=513.69); mass spectroscopy (MH⁺) 514.29.

EXAMPLE 286 Synthesis ofNtert-Butyl-N′-(N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L(4ethylphenyl)phenylglycinamiide

[2427] Following General Procedure AL and usingN-(3,5-difluorophenylacetyl)-L-alaine (from Example 82 above),4,4′-ethylbiphenylcarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=231-233C.).

[2428] C₃₁H₃₅N₃O₃F₂ (MW=513.69); mass spectroscopy (MH⁺) 514.29.

EXAMPLE 287 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-4(tert-butyl)phenylglycinamide

[2429] Following General Procedure AL and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),4-(tert-butyl)benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=280° C. (dec.)). The reaction was monitored bytlc (Rf=0.13 in 50% ethyl acetatelhexanes).

[2430] C₂₇H₃₅N₃O₃F₂ (MW=487.65); mass spectroscopy (MH⁺) 488.27.

EXAMPLE 288 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-3-(4chlorophenoxy)phenylglycinamide

[2431] Following General Procedure AL and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),3-(4-chlorophenoxy)benzaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and tert-butylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=192-195° C.).

[2432] C₂₉H₃₀N₃O₄F₂Cl (MW=558.07); mass spectroscopy (MH⁺) 558.20.

EXAMPLE 289 Synthesis ofN-Cyclohexyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-4(phenyl)phenylglycinamide

[2433] Following General Procedure AB and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above),4-biphenylcarboxaldehyde (Aldrich), (S)-(+)-α-methylbenzylamine(Aldrich) and cyclohexylisocyanide (Aldrich), the title compound wasprepared as a solid (mp=290-291° C.).

[2434] C₃₁H₃₃N₃O₃F₂ (MW=533.62); mass spectroscopy (MH⁺) 534.3.

EXAMPLE 290 Synthesis ofN-[N-(3,5-Difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-L-phenylglycinetert-Butyl Ester

[2435] Following General Procedure C and using 3,5-difluoromandelic acid(Fluorochem) and N-(L-alaninyl)-L-phenylglycine tert-butyl ester(prepared using N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butylester hydrochloride (Bachem) using General Procedure C, followed byremoval of the BOC group using General Procedure P), the title compoundwas prepared.

[2436] C₂₃H₂₆N2O₅F₂ (MW=479.53). Elemental analysis: Calc. (%) C, 61.60;H 5.84; N, 6.25. Found (%) C, 61.32; H, 6.02; N, 6.17.

EXAMPLE 291 Synthesis ofN-tert-Butyl-N′-[N-(3,5-Difluorophenyl-α,α-dinluoroacetyl)-L-alaninyl]-L-phenylglycinamide

[2437] Following General Procedure C and using3,5-difluorophenyl-α,α-difluoroacetic acid (from Example D23 above) andN-(L-alaninyl)-L-phenylglycine tert-butyl ester (prepared usingN-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl esterhydrochloride (Bachem) using General Procedure C, followed by removal ofthe BOC group using General Procedure P), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.39 in 30% ethylacetate/hexanes) and the product was purified by HPLC using 17% ethylacetate/hexanes as the eluent.

[2438] C₂₃H₂₄N₂O₄F₄ (MW=468.49); mass spectroscopy (MH⁺) 469.17.

EXAMPLE 292 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-ButylEster

[2439] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andD-phenylglycine tert-butyl ester (prepared from D-phenylglycine (Sigma)using General Procedure 3), the title compound was prepared. Thereaction was monitored by tlc (Rf=0.1 in 10% MeOH/CHCl₃).

[2440] NMR data was as follows:

[2441]¹H-nmr (DMSO-d₆): δ=8.64 (d, 1H), 8. 38 (d, 1H), 7.34 (m, 5H),7.09 (m, 1H), 6.99 (m, 2H), 5.27 (d, 1H), 4.45 (m, 1H), 3.32 (s, 2H)1.28 (s, 9H), 1. 18 (d, 3H).

[2442] Optical Rotation: [α]₂₀=−103.58 (c=1, MeOH).

[2443] C₂₃H₂₆N₂O₄F₂ (MW=432.47); mass spectroscopy (MH⁺) 433.

EXAMPLE 293 Synthesis ofN-[(S)-1-Oxo1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2444] By oxidation ofN-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(from Example 226 above) using Jones reagent in acetone, the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.7 in 9:1CHCl₃/MeOH) and the product was purified by flash chromatography using97:3 chloroform/methanol as the eluent.

[2445] NMR data was as follows:

[2446]¹H nmr (CDCl₃):=7.98 (m, 2H), 7.26 (m, 1H), 7.50 (m, 2H), 6.84 (m,2H), 6.72 (m, 1H), 6.25 (d, 1H), 5.49 (m, 3H), 4.54 (m, 3H), 3.54 (s,2H), 1.41 (d, 3H), 1.38 (d, 3H).

[2447] Optical Rotation: [α]₂₀=−106°@589 nm (c=1, MeOH).

[2448] C₂₀H₂₀F₂N₂O₃ (MW=374.39); mass spectroscopy (MH⁺) 374.

EXAMPLE 294 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L]-D,L(pyrid-3-yl)glycine tert-ButylEster

[2449] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andtert-butyl 2-amino-2-(3-pyridyl)acetate (prepared as described in Kolaret al., J. Heterocyclic Chem., 28, 171 (1991) and reference citedtherein), the title compound was prepared. The reaction was monitored bytlc (Rf=0.2 in 5% MeOH/CHCl₃) and the product was purified by flashchromatography using 5 % MeOH/CHCl₃ as the eluent.

[2450] NMR data was as follows:

[2451]¹H nmr (CDCl₃): δ=8.63 (m, 1H), 8.54 (m, 1H), 7.62 (m, 1H), 7.45(t, 1H), 7.26 (m, 1H), 6.82(m, 2H), 6.71 (m, 1H), 6.47 and 6.36 (d, 1H),5.42 (d, 1H), 4.59 (m,1H), 3.52 and 3.47 (two s, 2H), 1.38 and 1.36 (s,9H), 1.34 and 1.28 (two d, 3H).

[2452] C₂₂H₂₅N₃O₄F₂ (MW=433.46); mass spectroscopy (MH⁺) 434.

EXAMPLE 295 Synthesis of[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine

[2453] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and morpholine (Aldrich), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃)and the product was purified by flash chromatography using 5 %MeOH/CHCl₃ as the eluent.

[2454] NMR data was as follows:

[2455]¹H nmr (DMSO-d₆): δ=8.60 and 8.49 (two d's, 1H), 8.49 (m, 1H),7.25 (m, 5H), 7.18 (m, 2H), 6.95 (m, 1H), 5.82 (m, 1H), 4.38 (m, 1H),3.52 (m, 1O), 1.21 and 1.12 (two d's, 3H).

[2456] C₂₃H₂₅N₃O₄F₂ (MW=445.47); mass spectroscopy (MH⁺) 446.

EXAMPLE 296 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L(2-methoxy)phenylglycineMethyl Ester

[2457] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andmethyl 2-amino2-(2-methoxy)acetate (prepared from 2-methoxybenzaldehyde(Aldrich) using the Bucherer modification of the Strecker procedure asdescribed in J. P. Greenstein et al., “The Chemistry of Amino Acids”,Wiley: New York, 1961, Vol. 1, p. 698), the title compound was prepared.The reaction was monitored by tlc (Rf=0.3 in 10% MeOH/CHCl₃) and theproduct was purified by flash chromatography using 10% MeOH/CHCl₃ as theeluent.

[2458] NMR data was as follows:

[2459]¹H nmr (CDCl₃): δ=7.28 (m, 2H), 6.93 (d, 1H), 6.88 (m, 2H), 6.69(m, 2H), 6.34 (m, 1H), 5.67 (m, 1H), 4.52 (m, 1H), 3.81 (two s, 3H),3.68 (two s, 3H), 3.59 and 3.45 (two s, 3H) 1.41 and 1.28 (two d, 3H).

[2460] C₂₁H₂₂N₂O₅F₂ (MW 420.42); mass spectroscopy (MH⁺) 420.

EXAMPLE 297 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-ter-Butoxycarbonyl(hydroxyl amine) Ester

[2461] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and N-BOC hydroxyl amine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.35 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using2% MeOH/CHCl₃ as the eluent.

[2462] NMR data was as follows:

[2463]¹H nmr (CDCl₃): δ=7.79 (m, 1H), 7.41-7.28 (m, 5H), 6.78-6.59 (m,3H), 5.52 (m, 1H), 4.69 (m, 1H), 3.38 (two s, 1H), 1.38 (d, 3H), 1.30(s, 9H).

[2464] C₂₄H₂₇N₃O₆F₂ (MW=491.49); mass spectroscopy (MH⁺) 492.

EXAMPLE 298 Synthesis ofN-Neopentyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2465] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and neopentylamine (Aldrich), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl₃)and the product was purified by flash chromatography using 10%MeOH/CHCl₃ as the eluent.

[2466] NMR data was as follows:

[2467]¹H nmr (DMSO-d₆): δ=8.44 (m, 1H), 7.41 (m, 2H), 7.31 (m, 3H), 7.12(m, 1H), 6.99 (m, 2H), 5.50 (m, 1H), 4.47 (m, 1H), 3.52 (two s, 2H),2.84 (m, 2H), 1.22 (m, 3H), 0.71 (s, 9H).

[2468] C₂₄H₂₉N₃O₃F₂ (MW=460); mass spectroscopy (MH⁺) 460.

EXAMPLE 299 Synthesis ofN-Tetrahydrofurfuryl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2469] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and tetrahydrofurfurylamine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.4 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using10% MeOH/CHCl₃ as the eluent.

[2470] NMR data was as follows:

[2471]¹H nmr (DMSO-d₆): δ=8.41 (m, 2H), 7.32 (m, 5H), 7.08 (m, 1H), 6.99(m, 2H), 5.48 (m, 1H), 4.42 (m, 1H), 3.85-3.54 (m, 3H), 3.48 (two s,21), 3.14 (m, 2H), 1.76 (m, 4H), 1.21 (m, 3H).

[2472] C₂₄H₂₇N₃O₄F₂ (MW=459.49); mass spectroscopy (MH⁺) 460.

EXAMPLE 300 Synthesis ofN-Methoxy-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2473] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and methoxyanine hydrochloride (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf 0.35 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using10% MeOH/CHCl₃ as the eluent.

[2474] NMR data was as follows:

[2475]¹H-nmr (DMSO-d₆): δ=8.63 (m, 1H), 8.35 (m, 1H), 7.34 (m, 5H), 7.12(m, 1H), 6.99 (m, 2H), 5.23 (d, 1H), 4.42 (m, 1H), 3.58 (s, 3H), 3.51(two s, 2H), 1.22 (d, 3H).

[2476] C₂₀H₂₁N₃O₄F₂ (MW=405); mass spectroscopy (MH⁺) 405.

EXAMPLE 301 Synthesis of[N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyllazetidine

[2477] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and azetidine (Aldrich), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.6 in 10% MeOH/CHCl₃)and the product was purified by flash chromatography using 10%MeOH/CHCl₃ as the eluent.

[2478] NMR data was as follows:

[2479]¹H nmr (DMSO-d₆): δ=8.61 and 8.46 (two d, 1H), 8.33 (m, 1H), 7.34(m, 5H), 7.19 (m, 1H), 6.99 (m, 2H), 5.36 (two d, 1H), 4.42 (m, 1H),4.31 (m, 1H), 3.88 (m, 3H), 3.5 (two s, 2H), 2.36 (m, 2H), 1.18 (two d,3H).

[2480] C₂₂H₂₃N₃O₃F₂ (MW=415.44); mass spectroscopy (MH⁺) 416.

EXAMPLE 302 Synthesis ofN-Isobutyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2481] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and isobutylamine (Aldrich), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.65 in 10% MeOH/CHCl₃)and the product was purified by flash chromatography using 10%MeOH/CHCl₃ as the eluent.

[2482] NMR data was as follows:

[2483]¹H nmr (DMSO-d₆): δ=8.41 (m, 1H), 8.22 (m, 1H), 7.38 (m, 2H), 7.09(m, 1H), 6.98 (m, 2H), 5.52 (two d, 1H), 4.41 (m, 1H), 3.34 (two s, 2H),2.85 (s, 2H), 1.61 (m, 1H), 1.20 (m, 3H), 0.92 (m, 6H).

[2484] C₂₃H₂₇N₃O₃F₂ (MW=431.48); mass spectroscopy (MH⁺) 432.

EXAMPLE 303 Synthesis ofN-Cyclopropanemethyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2485] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and (aminomethyl)cyclopropane (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.25 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using10% MeOH/CHCl₃ as the eluent.

[2486] C₂₃H₂₅N₃O₃F₂ (MW=429.47); mass spectroscopy (MH⁺) 374.

EXAMPLE 304 Synthesis ofN-Methoxy-N-methyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2487] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and N-methoxy-N-methylamine hydrochloride (Aldrich),the title compound was prepared. The reaction was monitored by tlc(Rf=0.3 in 10% MeOH/CHCl₃) and the product was purified by flashchromatography using 2% MeOH/CHCl₃ as the eluent.

[2488] NMR data was as follows:

[2489]¹H nmr (DMSO-d₆): δ=8.65 and 8.53 (two d, 1H), 8.37 (m, 1H), 7.31(m, 5H), 7.12 (m, 1H), 6.98 (m, 2H), 5.91 and 5.82 (two d, 1H), 4.49 (m,1H), 3.60-3.42 (m, 5H), 3.08 (two s, 3H), 1.21 and 1.16 (two d, 3H).

[2490] C₂₁H₂₃N₃O₄F₂ (MW 419); mass spectroscopy (MH⁺) 420.

EXAMPLE 305 Synthesis ofN-2-Methylprop-2-enyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2491] Following General Procedure M and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 1-amino-2-methylprop-2-ene (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.45 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using 3% MeOH/CHCl₃ as the eluent.

[2492] NMR data was as follows:

[2493]¹H nmr (DMSO-d₆): δ=8.43 (m, 2H), 7.40 (m, 2H), 7.29 (m, 3H), 7.11(m, 1H), 6.98 (m, 2H), 5.46 (d, 1H), 4.68 (m, 2H), 4.42 (m, 1H), 3.6 (m,2H), 3.49 (s, 2H), 1.56 (s, 3H), 1.21 (d, 3H).

[2494] C₂₃H₂₅N₃O₃F₂ (MW=429.47); mass spectroscopy (MH⁺) 430.

EXAMPLE 306 Synthesis ofN-(Pyrid-3-yl)methyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2495] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 3-(aminomethyl)pyridine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.1 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using3% MeOH/CHCl₃ as the eluent.

[2496] NMR data was as follows:

[2497]¹H nmr (DMSO-d₆): δ=8.82 (m, 1H), 8.55 (m, 1H), 8.42 (m, 3H), 7.52(m, 1H), 7.35 (m, 5H), 7.10 (m, 1H), 6.99 (m, 2H), 5.43 (d, 2H), 4.44(m, 1H), 4.30 (bd, 2H) 3.52 (s, 2H) 1.26 (d, 3H).

[2498] C₂₃H₂₄N₄O₃F₂ (MW=466.49); mass spectroscopy (MH⁺) 467.

EXAMPLE 307 Synthesis ofN-(Pyrid-4yl)methyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2499] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 4-(aminomethyl)pyridine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.1 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using3% MeOH/CHCl₃ as the eluent.

[2500] NMR data was as follows:

[2501]¹H nmr (DMSO-d₆): δ=8.88 (m, 1H), 8.54 (d, 1H), 8.43 (m, 3H), 7.37(m, 4H), 7.12 (m, 3H), 6.9(m, 1H), 5.44 (d, 1H), 4.45 (m, 1H), 4.31 (d,2H), 3.51 (s, 2H), 1.25 (d, 3H).

[2502] C₂₃H₂₄N₄O₃F₂ (MW=466.49); mass spectroscopy (MH⁺) 467.

EXAMPLE 308 Synthesis ofN-Furfuryl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2503] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and furfurylanine (Aldrich), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.5 in 10% MeOH/CHCl₃)and the product was purified by flash chromatography using 3% MeOH/CHCl₃as the eluent.

[2504] NMR data was as follows:

[2505]¹H-nmr (DMSO-d₆): δ=8.66 (m, 1H), 8.45 (d, 1H), 8.39 (m, 1H), 7.57(s, 1H), 7.33 (m, 5H), 7.09 (m, 1H), 6.99 (m, 2H), 6.36 (m, 1H), 6.12(s, 1H), 5.41 (d, 1H), 4.22 (m, 1H), 3.52 (s, 2H) 1.24 (d, 3H).

[2506] C₂₄H₂₃N₃O₄F₂ (MW=455); mass spectroscopy (MH⁺) 456.

EXAMPLE 309 Synthesis of N-Cyclopentyl-N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2507] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and cyclopentylamine (Aldrich), the title compoundwas prepared. The product was purified by recrystallization fromethanol.

[2508] NMR data was as follows:

[2509]¹H nmr (DMSO-d₆): δ=8.32 (m, 2H), 8.16 (m, 1H), 7.33-7.20 (m, 5H),7.04 (m, 1H), 6.93 (m, 2H), 5.34 (d, 1H), 4.37 (m, 1H), 3.9 (m, 1H),3.49 (s, 2H), 1.80-1.29 (m, 8H), 1.19 (d, 3H).

[2510] C₂₄H₂₇N₃O₃F₂ (MW=443.49); mass spectroscopy (MH⁺) 444.

EXAMPLE 310 Synthesis ofN-1-Benzylpiperidin-4yl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2511] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 4-amino-1-benzylpiperdine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.2 in 10%MeOH/CHCl₃) and the product was purified by flash chromatography using 3% MeOH/CHCl₃ as the eluent.

[2512] NMR data was as follows:

[2513]¹H nmr (DMSO-d₆): δ=8.39 (m, 2H), 8.21 (m, 1H), 7.30 (m, 5H), 7.11(m, 1H), 6.98 (m, 2H), 5.39 (d, 1H), 4.21 (m, 1H), 3.54 (bm, 3H), 3.42(bs, 2H), 2.70 (bm, 2H), 1.89 (bm, 2H), 1.71 (bm, 2H), 1.42 (3H), 1.22(m, 3H).

[2514] C₃₁H₃₄N₄O₃F₂ (MW 548.64); mass spectroscopy (MH⁺) 548.

EXAMPLE 311 Synthesis ofN,N-Dimethyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2515] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and dimethylamine (Aldrich), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.65 in 10% MeOH/CHCl₃)and the product was purified by flash chromatography using 5% MeOH/CHCl₃as the eluent.

[2516] NMR data was as follows:

[2517]¹H nmr (DMSO-d₆): δ=8.13 and 8.01 (two d, 1H), 7.32 (m, 5H), 6.78(m, 2H), 6.63 (m, 1H), 5.88 (m, 1H), 4.72 (m, 1H), 3.45 (two s, 2H),2.94 (two s, 6H), 1.32 and 1.17 (two d, 3H).

[2518] C₂₁H₂₃N₃O₃F₂ (MW=403.43); mass spectroscopy (MH⁺) 404.

EXAMPLE 312 Synthesis ofN-2,2,6,6-Tetramethylpiperidin-4yl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2519] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 4-amino-2,2,6,6,-tetramethylpiperdine (Aldrich),the title compound was prepared. The reaction was monitored by tlc(Rf=0.2 in 2% MeOH/CHCl₃) and the product was purified by flashchromatography using 2% MeOH/CHCl₃ as the eluent.

[2520] NMR data was as follows:

[2521]¹H nmr (IMSO-d₆): δ=8.46 (d, 11H), 8.33 (d, 1H), 8.12 (bm, 1H),7.33 (m, 5H), 7.13 (m, 1H), 6.99 (m, 2H), 5.37 (d, 1H), 4.41 (m, 1H),3.98 (m,1H), 3.52 (s, 2H), 1.67 (bm, 1H), 1.44 (bm, 1H), 1.22 (d, 3H),1.01 (b m, 14H).

[2522] C₂₈H₃₆N₄O₃F₂ (MW=514.62); mass spectroscopy (MH⁺) 514.

EXAMPLE 313 Synthesis ofN-2-Methylcyclohexyl-N′-[N-(3,5-Difluorophenylacetyl)-alaninyl]-D,L-phenylglycinalmide

[2523] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 2-methylcyclohexylamine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.4 in 2%MeOH/CHCl₃).

[2524] NMR data was as follows:

[2525]¹H nmr (DMSO-d₆): δ=8.41 (m, 2H), 8.0 (m, 1H), 7.33 (m, 5H), 7.11(m, 1H), 6.99 (m, 2H), 5.35 (m, 1H), 4.41 (m, 1H), 3.52 ( s, 2H), 3.18(m,1H), 1.78-0.82 (m 11H), 0.81 (m, 3H).

[2526] C₂₆H₃₁N₃O₃F₂ (MW=472.5); mass spectroscopy (MH⁺) 472.

EXAMPLE 314 Synthesis ofN-4Methylcyclohexyl-N′-[N-(3,5-Dfluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2527] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 4-methylcyclohexylamine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.2 in 2%MeOH/CHCl₃) and the product was purified by flash chromatography using 2% MeOH/CHCl₃ as the eluent.

[2528] NMR data was as follows:

[2529]¹H nmr (DMSOd₆): δ=8.38 (m, 2H), 8.08 (m, 1H), 7.33 (m, 5H), 7.09(m, 1H), 7.01 (m, 2H), 5.54 and 5.36 (two d, 1H), 4.43 (m, 2H), 3.76 (m,1H), 3.52 (s, 2H), 1.79-1.17 (m, 11H), 0.84 (d, 3H).

[2530] C₂₆H₃₁N₃O₃F₂ (MW=472.5); mass spectroscopy (MH⁺) 472.

EXAMPLE 315 Synthesis ofN-1-Ethoxycarbonylpiperidin-4yl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2531] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and 4-amino-1-ethoxycarbonylpiperdine (Aldrich), thetitle compound was prepared. The reaction was monitored by tdc (Rf=0.2in 2% MeOH/CHCl₃) and the product was purified by flash chromatographyusing 2% MeOH/CHCl₃ as the eluent.

[2532] NMR data was as follows:

[2533]¹H nmr (DMSO-d₆): δ=8.42 (m, 2H), 8.23 (m, 1H), 7.33 (m, 5H), 7.09(m, 1H), 6.98 (m, 2H), 5.38 (m, 1H), 4.41 (m, 1H), 4.01 (q, 2H), 3.9-3.64 (m, 3H), 3.49 (s, 2H), 2.88 (bm, 2H), 1.75 (m,1H), 1.54 (m,1H), 1.2(m, 6H).

[2534] C₂₇H₃₂N₄O₅F₂ (MW=530.57); mass spectroscopy (MH⁺) 531.

EXAMPLE 316 Synthesis ofN-Methyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[2535] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-methyl-(S)-2-amino-2-phenylacetamide [CAS 129213-83-8], the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.2 in 5%MeOH/CHCl₃) and the product was purified by flash chromatography using5% MeOHICHCl₃ as the eluent.

[2536] NMR data was as follows:

[2537]¹H nmr (DMSO-d₆): δ=8.43 (m, 2H), 8.21 (m, 1H), 7.36 (m, 5H), 7.09(m, 1H), 6.95 (m, 2H), 5.36 (m, 1H), 4.40 (m, 1H), 3.41 (s, 2H), 2.56(d, 3H), 1.22 (d, 3H).

[2538] Optical Rotation: [α]₂₀=−67 (c=1, MeOH).

[2539] C₂₀H₂₁N₃O₃F₂.0.75 H₂O (MW=403.43); mass spectroscopy (MH⁺) 404.

EXAMPLE 317 Synthesis ofN-tert-Butoxy-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide

[2540] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and O-(tert-butoxy)hydroxylamine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.65 in 10%MeOH/CHCl₃).

[2541] NMR data was as follows:

[2542]¹H nmr (DMSO-d₆): δ=8.72 and 8.58 (two d, 1H), 8.39 (m, 1H), 7.37(m, 5H), 7.10 (m, 1H), 6.99 (m, 2H), 5.41 (m, 1H), 4.46 (m, 1H), 3.51(two s, 3H), 1.22 (m, 3H), 1.09 (s, 9H).

[2543] C₂₃H₂₇N₃O₄F₂ (MW=447.48); mass spectroscopy (MH⁺) 448.

EXAMPLE 318 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-Butyl(hydroxylaminne) Ester

[2544] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and N-(tert-butoxy)hydroxylamine (Aldrich), the titlecompound was prepared. The reaction was monitored by tlc (Rf=0.65 in 10%MeOH/CHCl₃).

[2545] C₂₃H₂₇N₃O₄F₂.0.25 H₂O (MW=447.48); mass spectroscopy (MH⁺) 448.

EXAMPLE 319 Synthesis ofN-[N-(3,5Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine Hydrazide

[2546] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinemethyl ester (2.0 g, 5.1 mmol) (from Example 111 above) was stirred inethanol (40 mL) and anhydrous hydrazine (0.3 mL, 10 mmol) (Aldrich) wasadded. The solution was heated at reflux for 12 hours and then allowedto cool to ambient temperature with stirring. A title compound wascollected as a white solid by filtration, washing with ethanol and dringin a vacuum oven (52% yield).

[2547] NMR data was as follows:

[2548]¹H nmr (DMSO-d₆): δ=1.20 (t, 3H), 5.41 (m, 1H).

[2549] C₁₉H₂₀N₃O₄F₂ (MW=390.39); mass spectroscopy (MH⁺) 390.

EXAMPLE 320 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycineAcetohydrazonate

[2550] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinehydrazide (0.5 g, 1.3 mmol) (from Example 319 above) was heated atreflux in triethylorthoacetate (40 mL). After 14 hours, the reactionmixture was concentrated under reduced pressure to afford the titlecompound as a white solid (84% yield). The reaction was monitored by tlc(Rf=0.65 in 10% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 5% MeOH/CHCl₃ as the eluent.

[2551] NMR data was as follows:

[2552]¹H nmr (DMSO-d₆): δ=4.03 (q, 2H), 5.54 (m, 1H).

[2553] C₂₃H₂₆N₄O₄F₂ (MW=460.49); mass spectroscopy (MH⁺) 460.

EXAMPLE 321 Synthesis of N-[N-(Phenylacetyl)-L-alaninyl]-L-phenylglycinetert-Butyl Ester

[2554] Following General Procedure C and using phenylacetic acid(Aldrich) and L-alaninyl-L-phenylglycine tert-butyl ester (preparedusing N-BOC-L-alanine (Sigma) and L-phenylglycine tert-butyl esterhydrochloride (Bachem) using General Procedure C, followed by removal ofthe BOC group using General Procedure P), the title compound wasprepared. The reaction was monitored by tlc (Rf=0.25 in 3% MeOH/CHCl₃)and the product was purified by crystallization fromchlorobutane/hexanes.

[2555] NMR data was as follows:

[2556] H-nmr (DMSO-d₆): δ=4.43 (m, 1H), 5.20 (d, 1H).

[2557] C₂₃H₂₈N₂O₄ (MW=396.49); mass spectroscopy (MH⁺) 397.

EXAMPLE 322 Synthesis ofN-4(phenyl)butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide

[2558] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-4-(phenyl)butyl-L-phenylglycinamide (prepared fromN-BOC-L-phenylglycine (Advanced Chemtech) and 4-phenylbutylamine(Aldrich) using General Procedure C, followed by removal of theBOC-group using General Procedure P), the title compound was prepared.The reaction was monitored by tlc (Rf=0.45 in 5% MeOH/CHCl₃) and theproduct was purified by trituration in water, followed by trituration inacetonitrile.

[2559] NMR data was as follows:

[2560]¹H nmr (DMSO-d₆): δ=4.42 (m, 1H), 5.37 (d, 1H).

[2561] C₂₉H₃₁N₃O₃F₂ (MW=507.5); mass spectroscopy (MH⁺) 507.

EXAMPLE 323 Synthesis ofN-3-(4Iodophenyl)propyl-N′-[N-(3,5-Difluorophenylacetyl)-alaninyl]-L-phenylglycinamide

[2562] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andN-3-(4-iodophenyl)propyl-L-phenylglycinamide (prepared fromN-BOC-L-phenylglycine (Advanced Chemtech) and3-(4-iodophenyl)propylamine (from Example D26 above) using GeneralProcedure C, followed by removal of the BOC-group using GeneralProcedure P), the title compound was prepared. The product was purifiedby trituration in water, followed by trituration in ethanol.

[2563] NMR data was as follows:

[2564] H-nmr (DMSO-d₆): δ=4.41 (q, 2H), 5.35 (m, 1H).

[2565] C₂₈H₂₈N₃O₄F₂I (MW=635.45); mass spectroscopy (MH⁺) 635.

EXAMPLE 324 Synthesis ofN-6(Amino)hexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideHydrochloride

[2566] Following General Procedure C and usingN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine (fromExample D25 above) and N-BOC-1,6-hexanediamine (Fluka), followed byremoval of the BOC-group using General Procedure P, the title compoundwas prepared. The product was isolated as a white solid.

[2567] NMR data was as follows:

[2568]¹H nmr (DMSO-d₆): δ=4.41 (m, 1H), 5.40 (t, 1H).

[2569] C₂₅H₃₂N₄O₃F₂ (MW=474.56); mass spectroscopy (MH⁺) 475.

EXAMPLE 325 Synthesis ofN-1-(Phthalimido)pent-2-yl-N′-(3,5-difluorophenylacetyl)-L-alaninamide

[2570] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and2-amino-l-phthalimidopentane hydrochloride (from Example D27 above), thetitle compound was prepared. The reaction was monitored by tlc (Rf=0.3in 5% MeOH/CHCl₃) and the product was purified by silica gelchromatography using 5% MeOH/CHCl₃ as the eluent, followed byrecrystallization from chlorobutane/acetonitrile.

[2571] NMR data was as follows:

[2572]¹H-nmr (DMSO-d₆): δ=4.1 (m, 2H), 7.83 (bs, 4H).

[2573] C₂₄H₂₅N₃O₄F₂ (MW=457.48); mass spectroscopy (MH⁺) 457.

EXAMPLE 326 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L(3,5-difluorophenyl)glycinyl]-L(3,5-difluorophenyl)glycineMethyl Ester

[2574] Following General Procedure AN and usingN-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycine (from ExampleD30 above) and L-3,5-difluorophenylglycine methyl ester (from ExampleD29 above), the title compound was prepared. The product was purified bycrystallization.

[2575] NMR data was as follows:

[2576]¹H nmr (DMSO-d₆): δ=9.40 (m, 1H), 9.0 (m, 1H), 6.8G7.70 (m, 9H),5.45 (d, 1H), 5.25 (m, 1H), 3.55-365 (m, 5H).

EXAMPLE 327 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-norleucine

[2577] Following General Procedure AF and using THF/H₂O (1:1) onN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine methyl ester,the title compound was prepared as a solid (mp=158.5-160.5° C.). Thereaction was monitored by tlc (Rf=0.29 in 10% MeOH/CH₂Cl₂).

[2578] NMR data was as follows:

[2579]¹H nmr (CD₃OD): δ=8.46 (bd, J=6.71, 1H), 8.25 (bd, J=7.69, 1H),7.00-6.79 (m, 3H), 4.50-4.35 (m, 2H), 3.61 (d, 2H), 1.94-1.79 (m, 1H),1.78-1.60 (m, (includes d at 1.40, J=7.14, 3H), 0.92 (m, 3H).

[2580]¹³C-nmr (CD₃OD): δ=176.0, 175.5, 172.9, 166.6, 166.5, 163.4,163.2, 141.7, 141.6, 141.5, 113.9, 113.8, 113.7, 113.6, 103.9, 103.6,103.2, 54.1, 50.9, 43.3, 32.9, 29.4, 23.8, 18.6, 14.8.

[2581] C₁₇H₂₂N₂O₄F₂ (MW=356.37); mass spectroscopy (MH⁺) 357.

EXAMPLE 328 Synthesis ofN-[N-(Cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine tert-Butyl Ester

[2582] Following General Procedure D and using cyclopentylacetic acid(Aldrich) and L-alaninyl-L-phenylglycine tert-butyl ester (prepared fromN-CBZ-L-alanine (Sigma) and L-phenylglycine tert-butyl esterhydrochloride (Bachem) using General Procedure C, followed by removal ofthe CBZ-group using General Procedure Y), the title compound wasprepared as a solid (mp=133-138° C.). The reaction was monitored by tlc(Rf=0.48 in 50% EtOAc/hexanes) and the product was purified by flashchromatography using 25-50% EtOAc/hexanes as the eluent.

[2583] NMR data was as follows:

[2584]¹H nmr (CDCl₃): δ=7/86 (bd, J=7.2 Hz, 1H), 7.30-7.15 (m, 5H), 6.81(bd, J=7.82 Hz, 1H), 5.34 (d, J=7.20 Hz, lHO, 4.72 (quint, J=7.2 Hz,1H), 2.04 (m, 3H), 1.75-1.28 (m (includes s at 1.34, 9H) 18H), 1.1-0.9(m, 2H).

[2585]¹³C-nmr (CDCl₃): δ=173.3, 172.8, 170.0, 137.1, 129.2, 128:6,127.7, 82.7, 57.7, 48.9, 43.0, 37.6, 32.9, 28.3, 25.4, 19.3.

[2586] C₂₂H₃₂N₂O₄ (MW 388.51); mass spectroscopy (MH⁺) 389.5.

EXAMPLE 329 Synthesis ofN-[N-(2,5Dichlorophenyhmercaptoacetyl)-L-alaninyl]-L-phenylglycineMethyl Ester

[2587] 2,5-Dichlorophenylmercaptoacetic acid (TCI America, Portland,Oreg.) (237 mg) was converted to the acid chloride as described in theGeneral Procedure A″ and utilized to acylate methylL-alaninyl-L-phenylglycinate as described in General Procedure B″. Thetitle compound (210 mg) was isolated as crystals from ethyl ether.

[2588] NMR data was as follows:

[2589]¹H nmr (DMSO-d₆) δ=8.85 (d, 1H), 8.20 (d, 1H), 6.70-7.45 (m, 8H),5.45 (d, 1H), 4.45-4.65 (m, 3H), 3.65 (s, 3H), 1.30 (d, 3H).

[2590] C₂₀H₂₀Cl₂N₂O₄S (MW=455.363) mass spectroscopy (MH⁺) 454.1.

[2591] Anal. Calcd. for C₂₀H₂₀Cl₂N₂O₄S: C, 52.75 H, 4.42 N, 6.15; Found:C, 53.58 H, 5.01, N, 6.34.

EXAMPLE 330 Synthesis ofN-[N-(3,4Dichlorophenyhmercptoacetyl)-L-alaninyl]-L-phenylglycine MethylEster

[2592] 3,4-Dichlorophenylmercaptoacetic acid (J. Med. Chem., 15(9),940-944 (1972)) (237 mg) was converted to the acid chloride as describedin the General Procedure A″ and utilized to acylate methylL-alaninyl-L-phenylglycinate as described in General Procedure B″. Thetitle compound (182 mg) was isolated as cyrstals from ethyl ether.

[2593] NMR data was as follows:

[2594]¹H nmr (DMSO-d₆) δ=8.8 (d, 1H), 8.40 (d, 1H), 7.25-7.65 (m, 8H),5.40 (d, 1H), 4.45 (m, 1H), 3.80 (m, 2H), 3.65 (s, 3H), 1.25 (d, 3H).

[2595] C₂₀H₂₀Cl₂N₂O₄S (MW=455.363); mass spectroscopy (MH⁺) 454.1

[2596] Anal. Calcd. for C₂₀H₂₀Cl₂N₂O₄S: C, 52.75 H, 4.42 N, 6.15; Found:C, 53.05 H, 4.67 N, 6.26.

EXAMPLE 331 Synthesis ofN-[N-(3,5-Difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine MethylEster

[2597] 3,5-Difluorophenoxyacetic acid [prepared by refluxing an aqueousmixture of 3,5-difluorophenol (Aldrich), 2-chloroacetic acid, and NaOH](188 mg) was converted to the acid chloride as described in the GeneralProcedure A″ and utilized to acylate methyl L-alaninyl-L-phenylglycinateas described in General Procedure B″. The title compound (210 mg) wasisolated as crystals from ethyl ether.

[2598] NMR data was as follows:

[2599]¹H nmr (DMSO-d₆) δ=8.85 (d, 1H), 8.20 (d, 1H), 6.70-7.45 (m, 8H),5.45 (d, 1H), 4.45-4.65 (m, 3H), 3.65 (s, 3H), 1.30 (d, 3H).

[2600] C₂₀H₂₀F₂N₂O₅ (MW=406.39); mass spectroscopy (MH⁺) 406.3.

[2601] Anal. Calcd. for C₂₀H₂₀F₂N₂O₅: C, 59.11 H, 4.96 N, 6.89; Found:C, 53.34 H, 4.80 N, 6.94.

EXAMPLE 332 Synthesis of MethylN-[N-(3,5-Difluorophenoxyacetyl)-L-alaninyl]-L2,3-dihydroisoindolel-carboxylate

[2602] Following General Procedure AN,L-2,3-Dihydro-1H-isoindole-1-carboxylic acid methyl ester hydrochloride(Gazz. Chim. Ital., 106 (1-2) p. 65-75 (1976)) (417 mg) was coupled toN-(3,5-difluorophenylacetyl-L-alanine (from Example B2) to provide thetitle compound (150 mg).

[2603] NMR data was as follows:

[2604]¹H nmr (DMSO-d₆) δ=8.55 (d, 1H), 6.85-7.45 (m, 7H), 5.50(m, 1H),4.95(s, 1H), 4.55-4.90(m, 2+H), 3.65 (m, 3H), 1.30 (m, 3H).

[2605] C₂₁H₂₀F₂N₂O₄ (MW=402.40); mass spectroscopy (MH⁺) 402.3.

EXAMPLE 333 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-1-amino1,3-diphenylpropane-2-one

[2606] To a solution of 200 mg ofN-methoxy-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide(from Example 304 above) in THF was added 1.91 mL of a 2M solution ofbenzyl magnesium bromide in THF (Aldrich) at 0° C. The reaction mixturewas strrred at ambient temperature for 72 hours, and was subsequentlyquenched by addition of water, The reaction mixture was partitionedbetween ethyl acetate and water and the organic phase was washed with 1NHCl solution. Following removal of solvent under reduced pressure, thecrude ketone was purified by chromatography on silica gel, eluting withethyl acetate, to afford 62 mg of the title compound as a 1:1 mixture ofphenyl diastereomers.

[2607] NMR data was as follows:

[2608]¹H-Nmr (CDCl₃) (approx 1:1 mixture of diastereomers) δ=7.2-7.5 (m,8H), 7.0-7.1 (m, 2H), 6.7-6.9 (m, 4H), 6.2 (m, 1H), 5.5(t, 1H), 3.5-3.6(m, 2H), 1.28-1.45 (doublets in 1:1 ratio, 3H).

EXAMPLE 334 Synthesis ofN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineThiocarboxamide

[2609] Step A—Preparation of t-butoxycarbonyl-phenylglycinethiocarboxamide:

[2610] To a suspension of 500 mg (2.00 mmol)t-butoxycarbonyl-L-phenylglycine carboxamide (prepared as in Example141) in 50 mL of dry toluene was added 808 mg (2.00 mmol) Lawesson'sreagent (Aldrich). The reaction mixture was heated to 95° C. for 5 min.Cooling to ambient temperature and dilution with 1:1 ethylacetate/hexanes resulted in precipitation of insoluble material. Removalof the soluble phase, followed by additional washing of the solids andcombination of the soluble phase, and removal of solvent afforded crudethiocarboxamide as a semisolid. Purification by chromatography on silicagel, eluting with ethyl acetate afforded 364 mg of thiocarboxamide.

[2611] Step B—Preparation of phenylglycine thiocarboxamide hydrobromide:

[2612] A solution of 364 mg of t-butoxycarbonyl phenylglycinethiocarboxamide in 4 mL 30% HBr in acetic acid was stirred for 1 hour.The volitile materials were removed under reduced pressure and the crudephenylglycine thiocarboxamide hydrobromide was obtained as a pale solid.The material was utilized without further purification.

[2613] To a stirred solution of 486 mg of(3,5-difluorophenylacetyl)-L-alanine (from B2) in 30 mL ofdichoromethane was added 383 mg of EDCI, 270 mg of HOBT hydrate,followed by 350 4L of diisopropylethylamine. To this suspension wasadded phenylglycine thiocarboxamide hydrobromide in dichloromethane. Thereaction mixture was stirred at ambient temperature for 72 hours. Thereaction mixture was partioned between water and dichloromethane and theorganic phase was washed with 1N HCl solution, followed by saturatedaqueous sodium bicarbonate solution. Removal of solvent afforded thecrude product, which was purified by chromatography on silica gel,eluting with ethyl acetate, to afford 271 mg of the title compound(approximately 3:2 mixture of phenylglycine diastereomers) as a palesolid.

[2614] NMR data was as follows:

[2615]¹H-Nmr (CDCl₃) (approx 3:2 mixture of diastereomers): δ=7.3-7.7(m, 81H), 6.7-6.8 (m, 4H).

EXAMPLE 335 Synthesis ofN-[N-(3,5-Difluorophenyl-2-oxoacetyl)-L-alaninyl]-L-phenylglycinetert-Butyl Ester

[2616] Following General Procedure C and usingL-alaninyl-L-phenylglycine tert-butyl ester (prepared as described inExample 321) and 3,5-difluorophenylglyoxylate (prepared as described inJ. Org. Chem., 45(14), 28883 (1980)), the title compound was prepared asa solid. The product was purified by slurrying with EtOAc/hexanes.

[2617] Elemental Anal.: Calc.(%) C, 61.88, H, 5.42, N, 6.27; Found: C,62.15, H, 5.51, N, 6.18.

EXAMPLE 336 Synthesis ofN-(2-Hydroxy-1-phenyleth-1-yl)-N′-[N-(3,5-Difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamide

[2618] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-alanine (prepared fromN-(3,5-difluorophenylacetyl)-L-phenylglycinyl-L-alanine ethyl ester) and(S)-phenylglycinol (Aldrich), the title compound was prepared (m.p.269-272° C.). The reaction was monitored by dtc (Rf=0.3 in 10%MeOH/CHCl₃) and the product was purified by chromatography using 10%MeOH/CHCl₃ as the eluent.

[2619] NMR data was as follows:

[2620]¹H-nmr (DMSO-d₆): δ=1.25 (d, 3H), 8.01 (d, 1H), 8.52 (d, 1H), 8.82(d, 1H).

[2621] Optical Rotation: [α]₂₀=−62.7@589 nm (c=1.02, DMSO).

[2622] C₂₇H₂₇N₃O₃F₂ (MW=495.53); mass spectroscopy (MH⁺) 496.

EXAMPLE 337 Synthesis ofN-(2-Hydroxyeth-1-yI)-N′-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-L-phenylglycinamide

[2623] Following General Procedure C and usingN-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) andL-phenylglycine (2-hydroxyethyl)amide hydrochloride (prepared fromN-BOC-L-phenylglycine (Bachem) and 2-aminoethanol (Aldrich) usingGeneral Procedure C, followed by removal of the BOC group using GeneralProcedure P), the title compound was prepared. The product was purifiedby chromatography using 10% MeOH/CHCl₃ as the eluent, followed bycrystallization from EtOH.

[2624] NMR data was as follows:

[2625]¹H nmr (DMSO-d₆): δ=1.22 (d, 3H), 5.42 (d, 1H).

[2626] Optical Rotation: [α]₂₀=+8.77@589 nm (c=1.03, DMSO).

[2627] C₂₁H₂₃N₃O₄F₂ (MW=419.43); mass spectroscopy (MH⁺) 420.

EXAMPLE 338 Synthesis of N-(4(4-Azido2-hydroxybenzamido)but-1-yl)-N′-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-L-phenylglycinamide

[2628] Following General Procedure A and usingN-(3,5-difluorophenylacetyl)-L-alanyl-L-phenylglycine (prepared asdescribed herein) and 4-(4-azidosalicylamido)butylamine (PierceChemical), the title compound was prepared as a light sensitive solid.The reaction was conducted under low light conditions and the reactionvessel was protected from light. The reaction was monitered by tlc(Rf=0.2 in 2.5% MeOH/dichloromethane).

[2629] NMR data was as follows:

[2630]¹H nmr (CD₃OH/CDCl₃): δ=7.72 (d, 2H), 7.30 (m, 5H), 6.84 (m, 2H),6.73 (m, 1H), 6.54 (m, 2H), 5.34 (s, 1H), 4.39 (q, 1H), 3.56 (s, 2H),3.31 (bs, 2H), 3.21 (bs, 2H), 1.57 (bs, 4H), 1.35 (d, 2H).

EXAMPLE 339 Synthesis ofN-(Methanesulfonyl)-N′-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-L-phenylalanamide

[2631] N-Cbz-L-Phenylalanine (Sigma) was coupled to N-hydroxysuccinimide(Aldrich) using DCC in dicloromethane. The resulting intermediate wasreacted with methanesulfonamide in DMF with diisopropylethylamine toprovide N-methanesulfonyl-N′-Cbz-L-phenylalanamide amide. The Cbz groupwas removed using General Procedure O and the resulting intermediate wascoupled to N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2above) using General Procedure B to give the title compound,m.p.=203-205° C.

EXAMPLES 340-407

[2632] By following the procedures set forth above, the followingadditional compounds were prepared:

[2633] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycinemethyl ester (Ex 340)

[2634] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl-L-(3-α-phenyl)prolinemethyl ester (Ex. 341)

[2635] N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidine methylester (Ex. 342)

[2636] methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorobenzothiophen-2-yl)acetate(Ex. 343)

[2637] t-butylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(thiazol-4-yl)propionate(Ex. 344)

[2638] t-butylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex.345)

[2639]N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide(Ex. 346)

[2640] N-[N-(3,⁴-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide(Ex. 347)

[2641] N-[N-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.348)

[2642] N-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.349)

[2643] N-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.350)

[2644] N-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.351)

[2645] N-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.352)

[2646] N-[N-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.353)

[2647]N-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamide(Ex. 354)

[2648] N-[N-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.355)

[2649] N-[N-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex.356)

[2650] N-[N-(1-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 357)

[2651] N-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 358)

[2652] N-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamide (Ex. 359)

[2653] N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine (Ex.360)

[2654]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(2-furanyl)acetamide(Ex. 361)

[2655] N′-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide(Ex. 362)

[2656]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfonamide(Ex. 363)

[2657]N″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide(Ex. 364)

[2658]N″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide(Ex. 365)

[2659]N′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide (Ex.366)

[2660]N″-methyl-N′-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide(Ex. 367)

[2661]N″-4-fluorobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide(Ex. 368)

[2662]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycineneopentyl ester (Ex. 369)

[2663]N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinemethyl ester (Ex. 370)

[2664]N-[N-(3,5difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycinemethyl ester (Ex. 371)

[2665]N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycinemethyl ester (Ex. 372)

[2666] N-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycinemethyl ester (Ex. 373)

[2667] N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methylester (Ex. 374)

[2668]N″-4-methylphenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide(Ex. 375)

[2669]N′-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide(Ex. 376)

[2670]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide(Ex. 377)

[2671] N′-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide(Ex. 378)

[2672]N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide(Ex. 379)

[2673]N′-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide(Ex. 380)

[2674] N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide(Ex. 381)

[2675]N-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide(Ex. 382)

[2676]N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(Ex. 383)

[2677]N-[1-phenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(Ex. 384)

[2678]N-[1-phenyl-2-oxo-pentan-1-yl]-N′-(3,5difluorophenylacetyl)-L-alaninamide(Ex. 385)

[2679]N-[1-phenyl-2-oxo-2-phenylethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide(Ex. 386)

[2680]N-[1-phenyl-2-oxo-butan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide(Ex. 387)

[2681]N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamide(Ex. 388)

[2682]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-α-hydroxyphenylalaninemethyl ester (Ex. 389)

[2683] N″-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide (Ex.390)

[2684]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinet-butyl ester (Ex. 391)

[2685]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycinet-butyl ester (Ex. 392)

[2686] [N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline)methyl ester (Ex. 393)

[2687]N″-t-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylphenylglycinamide(Ex. 394)

[2688]N″-t-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylacetenyl)phenylglycinamide(Ex. 395)

[2689]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide(Ex. 396)

[2690]N-[1,3-diphenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(Ex. 397)

[2691]N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(Ex. 398)

[2692]N-[1-phenyl-2-oxo-hexan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamide(Ex. 399)

[2693] N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N′-(3,5ifluorophenylacetyl)-L-alaninamide(Ex. 400)

[2694]N″-n-hexyl-6biotinarnidyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl-D,L-phenylglycinthioamide(Ex. 401)

[2695] N′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine (Ex.402)

[2696] N′-[N-(2-t-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycinemethyl ester (Ex. 403)

[2697] N″-t-butylN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide(Ex. 404)

[2698] N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycinemethyl ester (Ex. 405)

[2699]N′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine(Ex. 406)

[2700]N′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycinet-butyl ester (Ex. 407)

EXAMPLE 408

[2701] Following the procedures set forth above, the following compoundsof formula I were or could be prepared:

[2702] R¹ is 3,5-difluorophenyl; X′ and X″ are hydrogen; R² is methyl;R³ is hydrogen; R⁴ is p-fluorophenyl; R⁵ is hydrogen; Z is a bond, X is—C(O)OCH₂C(CH₃)₃; and n is 1;

[2703] R¹ is 3,5-difluorophenyl; X′ and X″ are hydrogen; R² is methyl;R³ is hydrogen; R⁴ is p-(phenyl)phenyl; R⁵ is hydrogen; X is—C(O)NHC(CH₃)₃; Z is abond; and n is 1;

[2704] R¹ is cyclopentyl; X′ and X″ are hydrogen; R² is methyl; R³ ishydrogen; R⁴ is phenyl; R⁵ is hydrogen; X is —C(O)OC(CH₃)₃; Z is a bond;and n is 1;

[2705] R¹ is cyclopropyl; X′ and X″ are hydrogen; R² is methyl; R³ ishydrogen; R⁴ is phenyl; R⁵ is hydrogen; X is —C(O)OC(CH₃)₃; Z is a bond;and n is 1; and

[2706] R¹ is 3,5-difluorophenyl; X′ and X″ are hydrogen; R² is methyl;R³ is hydrogen; R⁴ is phenyl; R⁵ is hydrogen; X is —C(O)OCH₂C(CH₃)₃; Zis a bond; and n is 1.

EXAMPLE 409 Cellular Screen for the Detection of Inhibitors of β-AmyloidProduction

[2707] Numerous compounds of formula I above were assayed for theirability to inhibit β-amyloid production in a cell line possessing theSwedish mutation. This screening assay employed cells (K293=human kidneycell line) which were stably transfected with the gene for amyloidprecursor protein 751 (APP751) containing the double mutationLys₆₅₁Met₆₅₂ to Asn₆₅₁Leu₆₅₂ (APP751 numbering) in the manner describedin International Patent Application Publication No. 94/10569⁸ and Citronet al.¹². This mutation is commonly called the Swedish mutation and thecells, designated as “293 751 SWE”, were plated in Corning 96-wellplates at 1.5-2.5×10⁴ cells per well in Dulbecco's minimal essentialmedia plus 10% fetal bovine serum. Cell number is important in order toachieve β-amyloid ELISA results within the linear range of the assay(˜0.2 to 2.5 ng per mL).

[2708] Following overnight incubation at 37° C. in an incubatorequilibrated with 10% carbon dioxide, media were removed and replacedwith 200 μL of a compound of formula I (drug) containing media per wellfor a two hour pretreatment period and cells were incubated as above.Drug stocks were prepared in 100% dimethylsulfoxide such that at thefinal drug concentration used in the treatment, the concentration ofdimethylsulfoxide did not exceed 0.5% and, in fact, usually equaled0.1%.

[2709] At the end of the pretreatment period, the media were againremoved and replaced with fresh drug containing media as above and cellswere incubated for an additional two hours. After treatment, plates werecentrifuged in a Beckman GPR at 1200 rpm for five minutes at roomtemperature to pellet cellular debris from the conditioned media. Fromeach well, 100 μL of conditioned media or appropriate dilutions thereofwere transferred into an ELISA plate precoated with antibody 26614against amino acids 13-28 of β-amyloid peptide as described inInternational Patent Application Publication No. 94/105698 and stored at4° C overnight. An ELISA assay employing labelled antibody 6C6¹⁴ againstamino acids 1-16 of β-amyloid peptide was run the next day to measurethe amount of β-amyloid peptide produced.

[2710] Cytotoxic effects of the compounds were measured by amodification of the method of Hansen, et al.¹³. To the cells remainingin the tissue culture plate was added 25 μL of a3,(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) stocksolution (5 mg/mL) to a final concentration of 1 mg/mL. Cells wereincubated at 37° C. for one hour, and cellular activity was stopped bythe addition of an equal volume of MTT lysis buffer (20% w/v sodiumdodecylsulfate in 50% dimethylformamide, pH 4.7). Complete extractionwas achieved by overnight shaking at room temperature. The difference inthe OD_(562nm) and the OD_(650nm) was measured in a Molecular Device'sUV_(max) microplate reader as an indicator of the cellular viability.

[2711] The results of the β-amyloid peptide ELISA were fit to a standardcurve and expressed as ng/mL β-amyloid peptide. In order to normalizefor cytotoxicity, these results were divided by the MTT results andexpressed as a percentage of the results from a drug free control. Allresults are the mean and standard deviation of at least six replicateassays.

[2712] The test compounds were assayed for β-amyloid peptide productioninhibition activity in cells using this assay. The results of this assaydemonstrate that, each of the compounds within this invention testedreduced β-amyloid peptide production by at least 30% as compared tocontrol.

EXAMPLE 410 In Vivo Suppression of β-Amyloid Release and/or Synthesis

[2713] This example illustrates how the compounds of this inventioncould be tested for in vivo suppression of β-amyloid release and/orsynthesis. For these experiments, 3 to 4 month old PDAPP mice are used[Games et al., (1995) Nature 373:523-527]. Depending upon which compoundis being tested, the compound is usually formulated at either 5 or 10mg/ml. Because of the low solubility factors of the compounds, they maybe formulated with various vehicles, such as corn oil (Safeway, SouthSan Francisco, Calif.); 10% EtOH in corn oil (Safeway);2-hydroxypropyl-β-cyclodextrin (Research Biochemicals International,Natick Mass.); and carboxy-methyl-cellulose (Sigma Chemical Co., St.Louis Mo.). Specifically, for example 141 the vehicle wascarboxy-methyl-cellulose (Sigma).

[2714] The mice are dosed subcutaneously with a 26 gauge needle and 3hours later the animals are euthanized via CO₂ narcosis and blood istaken by cardiac puncture using a 1 cc 25G ⅝″ tuberculin syringe/needlecoated with solution of 0.5 M EDTA, pH 8.0. The blood is placed in aBecton-Dickinson vacutainer tube containing EDTA and spun down for 15minutes at 1500 ×g at 5° C. The brains of the mice are then removed andthe cortex and hippocampus are dissected out and placed on ice.

[2715] 1. Brain Assay

[2716] To prepare hippocampal and cortical tissue for enzyme-linkedimmunosorbent assays (ELISAs) each brain region is homogenized in 10volumes of ice cold guanidine buffer (5.0 M guanidine-HCl, 50 mMTris-HCl, pH 8.0) using a Kontes motorized pestle (fisher, PittsburghPa.). The homogenates are gently rocked on a rotating platform for threeto four hours at room temperature and stored at −20° C. prior toquantitation of β-amyloid.

[2717] The brain homogenates are diluted 1:10 with ice-cold caseinbuffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodiumazide, 20 μg/ml aprotinin, 5 mM EDTA, pH 8.0, 10 μg/ml leupeptin],thereby reducing the final concentration of guanidine to 0.5 M, beforecentrifugation at 16,000 ×g for 20 minutes at 4° C. The β-amyloidstandards (1-40 or 1-42 amino acids) were prepared such that the finalcomposition equaled 0.5 M guanidine in the presence of 0.1% bovine serumalbumin (BSA).

[2718] The total β-amyloid sandwich ELISA, quantitating both β-amyloid(aa 1-40) and β-amyloid (aa 1-42) consists of two monoclonal antibodies(mAb) to β-amyloid. The capture antibody, 26614, is specific to aminoacids 13 - 28 of β-amyloid. The antibody 3D6¹⁵, which is specific toamino acids 1-5 of β-amyloid, is biotinylated and served as the reporterantibody in the assay. The 3D6 biotinylation procedure employs themanufacturer's (Pierce, Rockford Ill.) protocol for NHS-biotin labelingof immunoglobulins except that 100 mM sodium bicarbonate, pH 8.5 bufferis used. The 3D6 antibody does not recognize secreted amyloid precursorprotein (APP) or full-length APP but detects only β-amyloid species withan amino terminal aspartic acid. The assay has a lower limit ofsensitivity of ˜50 pg/ml (11 pM) and shows no cross-reactivity to theendogenous murine β-amyloid peptide at concentrations up to 1 ng/ml.

[2719] The configuration of the sandwich ELISA quantitating the level ofβ-amyloid (aa 1-42) employs the mAb 21F12¹⁵ (which recognizes aminoacids 33-42 of β-amyloid) as the capture antibody. Biotinylated 3D6 isalso the reporter antibody in this assay which has a lower limit ofsensitivity of ˜125 pg/ml (28 pM).

[2720] The 266 and 21F12 capture mAbs are coated at 10 μg/ml into 96well immunoassay plates (Costar, Cambidge Mass.) overnight at roomtemperature. The plates are then aspirated and blocked with 0.25% humanserum albumin in PBS buffer for at least 1 hour at room temperature,then stored desiccated at 4° C. until use. The plates are rehydratedwith wash buffer (Tris-buffered saline, 0.05% Tween 20) prior to use.The samples and standards are added to the plates and incubatedovernight at 4° C. The plates are washed ≧3 times with wash bufferbetween each step of the assay. The biotinylated 3D6, diluted to 0.5μg/ml in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH7.4) is incubated in the well for 1 hour at room temperature. Avidin-HRP(Vector, Burlingame Calif.) diluted 1:4000 in casein incubation bufferis added to the wells for 1 hour at room temperature. The colorimetricsubstrate, Slow TMB-ELISA (Pierce, Cambridge Mass.), is added andallowed to react for 15 minutes, after which the enzymatic reaction isstopped with addition of 2 N H₂SO₄. Reaction product is quantified usinga Molecular Devices Vmax (Molecular Devices, Menlo Park Calif.)measuring the difference in absorbance af 450 nm and 650 nm.

[2721] 2. Blood Assay

[2722] The EDTA plasma is diluted 1:1 in specimen diluent (0.2 gm/lsodium phosphate.H₂O (monobasic), 2.16 gm/1 sodium phosphateo7H₂O(dibasic), 0.5gm/1 thimerosal, 8.5 gm/I sodium chloride, 0.5 mlTritonX-405, 6.0 g/l globulin-free bovine serum albumin; and water). Thesamples and standards in specimen diluent are assayed using the totalβ-amyloid assay (266 capture/3D6 reporter) described above for the brainassay except the specimen diluent was used instead of the caseindiluents described.

[2723] From the foregoing description, various modifications and changesin the composition and method will occur to those skilled in the art.All such modifications coming within the scope of the appended claimsare intended to be included therein.

What is claimed is:
 1. A method for inhibiting β-amyloid peptide releaseand/or its synthesis in a cell which method comprises administering tosuch a cell an amount of a compound or a mixture of compounds effectivein inhibiting the cellular release and/or synthesis of β-amyloid peptidewherein said compounds are represented by formula I:

wherein R¹ is selected from the group consisting of alky, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R² isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclic; each R³ is independentlyselected from the group consisting of hydrogen and methyl and R³together with R⁴ can be fused to form a cyclic structure of from 3 to 8atoms which is optionally fused with an aryl or heteroaryl group; eachR⁴ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocyclic, substituted alkyl, substituted alkenyl and substitutedalkynyl; each R⁵ is selected from hydrogen and methyl or together withR⁴ forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selectedfrom the group consisting of —C(O)Y and —C(S)Y where Y is selected fromthe group consisting of (a) alkyl or cycloalkyl, (b) substituted alkylwith the proviso that the substitution on said substituted alkyl do notinclude α-haloalkyl, α-diazoalkyl, α—OC(O)alkyl, or α—OC(O)aryl groups,(c) alkoxy or thioalkoxy, (d) substituted alkoxy or substitutedthioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substitutedalkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ orR″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclicgroup having from 2 to 8 carbon atoms optionally containing 1 to 2additional heteroatoms selected from oxygen, sulfur and nitrogen andoptionally substituted with one or more alkyl, alkoxy or carboxylalkylgroups, (j) —NHSO₂—R⁸ where R⁸ is selected from alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic, (k) —NR⁹NR¹⁰R¹⁰ where R⁹ is hydrogen or alkyl, and eachR¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclic, and (l) —ONR⁹[C(O)O]_(z)R¹⁰ where z is zero or one, R⁹ andR¹⁰ are as defined above; X can also be —CR⁶R⁶Y′ where each R⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′is selected from the group consisting of hydroxyl, amino, thiol, alkoxy,substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R⁷ —SSR⁷,—SSC(O)R⁷ where R⁷ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X′ ishydrogen, hydroxy, or fluoro; X″ is hydrogen, hydroxy or fluoro, or X′and X″ together form an oxo group, Z is selected from the groupconsisting of a bond covalently linking R¹ to —CX′X″—, oxygen andsulfur; n is an integer equal to 1 or 2; and pharmaceutically acceptablesalts thereof with the provisos that: A. when R¹ is phenyl or3-nitrophenyl, R² is methyl, R³ is hydrogen, R⁴ is —CH(OH)CH₃, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—C(O)OH; B. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁴ is—CH(OH)CH₃ derived from D-threonine, R¹ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH₃;C. when R¹ is phenyl, R² is methyl, R⁴ is benzyl, R¹ is hydrogen, X ismethoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1, thenR³ is not methyl; D. when R¹ is iso-propyl, R² is —CH₂C(O)NH₂, R³ ishydrogen, R⁴ is iso-butyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; E. when R¹ is phenyl, R² ismethyl, R¹ is hydrogen, X is —C(O)OCH₃, X′ and X″ are hydrogen, Z is abond, and n is 1, then R³, the nitrogen atom attached to R³, and R⁴ donot form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. whenR¹ is phenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is—C(O)OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ isnot 4-amino-n-butyl; G. when R¹ is 3-nitrophenyl, R² is methyl, R³ ishydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)NH₂ or —CH₂OH; H. when R¹ isphenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is —CH₂OCH₃, X′and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ is not benzyl orethyl; I. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is methyl, R⁴is methyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is1, then X is not —CHOH+; J. when R¹ is 3,5-difluorophenyl, R² is methyl,R³ is hydrogen, R⁴ is phenyl derived from D-phenylglycine, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—CHOHφ or —CH₂OH; K. when R¹ is N-(2-pyrrolidinonyl), R₂ is methyl, R₃is hydrogen, R₄ is benzyl; R¹ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; L. when R¹ is3,5-difluorophenyl, R² is methyl derived from D-alanine, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R¹ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl; M. whenR¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is hydrogen,R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then Xis not —CH₂OH; N. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ ishydrogen, R⁴ is 4-phenylphenyl, R⁵ is hydrogen, X′ and X″ are hydrogen,Z is a bond, and n is 1, then X is not —C(O)NHC(CH)₃; and O. when R¹ is3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is phenyl derivedfrom D-phenylglycine, R¹ is hydrogen, X′ and X″ are hydrogen, Z is abond, and n is 1, then X is not —C(O)NHCH(CH₃)φ.
 2. A method forpreventing the onset of AD in a patient at risk for developing AD whichmethod comprises administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically inert carrier and an effectiveamount of a compound or a mixture of compounds of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alky, substitutedalkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R² isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclic; each R³ is independentlyselected from the group consisting of hydrogen and methyl and R³together with R⁴ can be fused to form a cyclic structure of from 3 to 8atoms which is optionally fused with an aryl or heteroaryl group; eachR⁴ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocyclic, substituted alkyl, substituted alkenyl and substitutedalkynyl; each R⁵ is selected from hydrogen and methyl or together withR⁴ forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selectedfrom the group consisting of —C(O)Y and —C(S)Y where Y is selected fromthe group consisting of (a) alkyl or cycloalkyl, (b) substituted alkylwith the proviso that the substitution on said substituted alkyl do notinclude α-haloalkyl, α-diazoalkyl, α—OC(O)alkyl, or α—OC(O)aryl groups,(c) alkoxy or thioalkoxy, (d) substituted alkoxy or substitutedthioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)—NR′R″where R′ and R″ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substitutedalkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ orR″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclicgroup having from 2 to 8 carbon atoms optionally containing 1 to 2additional heteroatoms selected from oxygen, sulfur and nitrogen andoptionally substituted with one or more alkyl, alkoxy or carboxylalkylgroups, (j) —NHSO₂-R⁸ where R⁸ is selected from alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic, (k) —NR⁹NR¹⁰R¹⁰ where R⁹ is hydrogen or alkyl, and eachR¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclic, and (l) —ONR⁹[C(O)O]_(z)R¹⁰ where z is zero or one, R⁹ andR¹⁰ are as defined above; X can also be —CR⁶R⁶Y′&0 where each R⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′is selected from the group consisting of hydroxyl, amino, thiol, alkoxy,substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R⁷, —SSR⁷,—SSC(O)R⁷ where R⁷ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X′ ishydrogen, hydroxy, or fluoro; X″ is hydrogen, hydroxy or fluoro, or X′and X″ together form an oxo group, Z is selected from the groupconsisting of a bond covalently linking R¹ to —CX′X″—, oxygen andsulfur; n is an integer equal to 1 or 2; and pharmaceutically acceptablesalts thereof with the provisos that: A. when R¹ is phenyl or3-nitrophenyl, R² is methyl, R³ is hydrogen, R⁴ is —CH(OH)CH₃, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—C(O)OH; B. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁴ is—CH(OH)CH₃ derived from D-threonine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH₃;C. when R¹ is phenyl, R² is methyl, R⁴ is benzyl, R⁵ is hydrogen, X ismethoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1, thenR³ is not methyl; D. when R¹ is iso-propyl, R² is —CH₂C(O)NH₂, R³ ishydrogen, R⁴ is iso-butyl, R⁵ is hydrogen, X′ and XX are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; E. when R¹ is phenyl, R² ismethyl, R⁵ is hydrogen, X is —C(O)OCH₃, X′ and X″ are hydrogen, Z is abond, and n is 1, then R³, the nitrogen atom attached to R³, and R⁴ donot form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. whenR¹ is phenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is—C(O)OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ isnot 4-amino-n-butyl; G. when R¹ is 3-nitrophenyl, R² is methyl, R³ ishydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)NH₂ or —CH₂OH; H. when R¹ isphenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is —CH₂OCH₃, X′and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ is not benzyl orethyl; I. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is methyl, R⁴is methyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is1, then X is not —CHOHφ; J. when R¹ is 3,5-difluorophenyl, R² is methyl,R³ is hydrogen, R⁴ is phenyl derived from D-phenylglycine, R5 ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—CHOHφ or —CH₂OH; K. when R¹ is N-(2-pyrrolidinonyl), R₂ is methyl, R₃is hydrogen, R⁴ is benzyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; L. when R¹ is3,5-difluorophenyl, R² is methyl derived from D-alanine, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl; M. whenR¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is hydrogen,R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then Xis not —CH₂OH; N. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ ishydrogen, R⁴ is 4-phenylphenyl, R⁵ is hydrogen, X′ and X″ are hydrogen,Z is a bond, and n is 1, then X is not —C(O)NHC(CH)₃; and O. when R¹ is3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is phenyl derivedfrom D-phenylglycine, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is abond, and n is 1, then X is not —C(O)NHCH(CH₃)φ.
 3. A method fortreating a patient with AD in order to inhibit further deterioration inthe condition of that patient which method comprises administering tosaid patient a pharmaceutical composition comprising a pharmaceuticallyinert carrier and an effective amount of a compound or a mixture ofcompounds of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R² isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclic; each R³ is independentlyselected from the group consisting of hydrogen and methyl and R³together with R⁴ can be fused to form a cyclic structure of from 3 to 8atoms which is optionally fused with an aryl or heteroaryl group; eachR⁴ is independently selected from the group consisting of hydrogen,alky, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocyclic, substituted alky, substituted alkenyl and substitutedalkynyl; each R⁵ is selected from hydrogen and methyl or together withR⁴ forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selectedfrom the group consisting of —C(O)Y and —C(S)Y where Y is selected fromthe group consisting of (a) alkyl or cycloalkyl, (b) substituted alkylwith the proviso that the substitution on said substituted alkyl do notinclude α-haloalkyl, α-diazoalkyl, α—OC(O)alkyl, or α—OC(O)aryl groups,(c) alkoxy or thioalkoxy, (d) substituted alkoxy or substitutedthioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substitutedalkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ orR″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclicgroup having from 2 to 8 carbon atoms optionally containing 1 to 2additional heteroatoms selected from oxygen, sulfur and nitrogen andoptionally substituted with one or more alkyl, alkoxy or carboxylalkylgroups, (j) —NHSO₂—R⁸ where R⁸ is selected from alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic, (k) —NR⁹NR¹⁰R¹⁰ where R⁹ is hydrogen or alkyl, and eachR¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclic, and (l) —NR⁹[C(O)O]_(z)R¹⁰ where z is zero or one, R⁹ andR¹⁰ are as defined above; X can also be —CR⁶R⁶Y′ where each R⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′is selected from the group consisting of hydroxyl, amino, thiol, alkoxy,substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R⁷, —SSR⁷,—SSC(O)R⁷ where R⁷ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X′ ishydrogen, hydroxy, or fluoro; X″ is hydrogen, hydroxy or fluoro, or X′and X″ together form an oxo group, Z is selected from the groupconsisting of a bond covalently linking R¹ to —CX′X″—, oxygen andsulfur; n is an integer equal to 1 or 2; and pharmaceutically acceptablesalts thereof with the provisos that: A. when R¹ is phenyl or3-nitrophenyl, R² is methyl, R³ is hydrogen, R⁴ is —CH(OH)CH₃, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—C(O)OH; B. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁴ is—CH(OH)CH₃ derived from D-threonine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH₃;C. when R¹ is phenyl, R² is methyl, R⁴ is benzyl, R⁵ is hydrogen, X ismethoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1, thenR³ is not methyl; D. when R¹ is iso-propyl, R² is —CH₂C(O)NH₂, R³ ishydrogen, R⁴ is iso-butyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; E. when R¹ is phenyl, R² ismethyl, R⁵ is hydrogen, X is —C(O)OCH₃, X′ and X″ are hydrogen, Z is abond, and n is 1, then R³, the nitrogen atom attached to R³, and R⁴ donot form 1,2,3,4-tetrahydroiso-quinolin-2-yl or pyrrolidin-2-yl; F. whenR¹ is phenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is—C(O)OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ isnot 4-amino-n-butyl; G. when R¹ is 3-nitrophenyl, R² is methyl, R³ishydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)NH₂ or —CH₂OH; H. when R¹ isphenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is —CH₂OCH₃, X′and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ is not benzyl orethyl; I. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is methyl, R⁴is methyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is1, then X is not —CHOHφ; J. when R¹ is 3,5-difluorophenyl, R² is methyl,R³ is hydrogen, R⁴ is phenyl derived from D-phenylglycine, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—CHOHφ or —CH₂OH; K. when R₁ is N-(2-pyrrolidinonyl), R₂ is methyl, R₃is hydrogen, R₄ is benzyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; L. when R¹ is3,5-difluorophenyl, R² is methyl derived from D-alanine, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl; M. whenR¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is hydrogen,R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then Xis not —CH₂OH; N. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ ishydrogen, R⁴ is 4-phenylphenyl, R5 is hydrogen, X′ and X″ are hydrogen,Z is a bond, and n is 1, then X is not —C(O)NHC(CH)₃; and O. when R¹ is3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is phenyl derivedfrom D-phenylglycine, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is abond, and n is 1, then X is not —C(O)NHCH(CH₃)φ.
 4. The method accordingto claim 1, 2 or 3 wherein R¹ is an unsubstituted aryl group and Z is abond covalently linking R¹ to —CX′X″—.
 5. The method according to claim4 wherein the unsubstituted R¹ aryl group is selected from the groupconsisting of phenyl, 1-naphthyl and 2-naphthyl.
 6. The method accordingto claim 1, 2 or 3 wherein R¹ is a substituted aryl group and Z is abond covalently linking R¹ to —CX′X″—.
 7. The method according to claim6 wherein said substituted aryl group is a mono-substituted,di-substituted or tri-substituted phenyl group.
 8. The method accordingto claim 7 wherein the substituted phenyl groups are selected from thegroup consisting of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl,3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl,3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxy-phenyl,2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl,2,3,4,5, 6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl,3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,2,4-dichlorophenyl, and 2,5-difluorophenyl.
 9. The method according toclaim 1, 2 or 3 wherein R¹ is an alkaryl group and Z is a bondcovalently linking R¹ to —CX′X″—.
 10. The method according to claim 9wherein the R¹ alkaryl group is selected from the group consisting ofbenzyl, 2-phenylethyl, and 3-phenyl-n-propyl.
 11. The method accordingto claim 1, 2 or 3 wherein R¹ is selected from the group consisting ofalkyl, alkenyl, cycloalkyl and cycloalkenyl groups and Z is a bondcovalently linking R¹ to —CX′X″—.
 12. The method according to claim 11wherein R¹ is alkyl.
 13. The method according to claim 11 wherein R¹ iscycloalkyl.
 14. The method according to claim 11 wherein R¹ is alkenyl.15. The method according to claim 11 wherein R¹ is cycloalkenyl.
 16. Themethod according to claim 11 wherein the R¹ alkyl, cycloalkyl, alkenyland cycloalkenyl groups are selected from the group consisting ofiso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,—CH₂CH═CH₂, —CH₂CH═CH(CH2)₄CH₃, cyclopropyl, cyclobutyl, cyclohexyl,cyclopentyl, cyclohex-1-enyl, —CH₂-cyclopropyl, —CH₂-cyclobutyl,—CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl,aminomethyl, and N-tert-butoxycarbonylaminomethyl.
 17. The methodaccording to claim 1, 2 or 3 wherein R¹ is selected from the groupconsisting of heteroaryl and substituted heteroaryl groups and Z is abond covalently linking R¹ to —CX′X″—.
 18. The method according to claim17 wherein the R¹ heteroaryl and substituted heteroaryl groups areselected from the group consisting of pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl),chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl,benzothiazol4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl,thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl,3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl.
 19. Themethod according to claim 1, 2 or 3 wherein R² is selected from thegroup consisting of alkyl, substituted alkyl, cycloalkyl, aryl,heteroaryl and heterocyclic.
 20. The method according to claim 9 whereinR² is selected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl,3,5-difluoro-phenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl,cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, —CH₂CH₂SCH₃,—CH₂OCH₂φ, —CH(CH₃)OCHi2 , —CH(OH)CH₃ and —CH₂OH.
 21. The methodaccording to claim 1, 2 or 3 wherein X′ and X″ are hydrogen and Z is abond covalently linking R′ to —CX′X″—.
 22. The method according to claim21 wherein R³ is selected from the group consisting of hydrogen, methylor together with R⁴ and the nitrogen to which R³ is attached formspyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl,4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. 23.The method according to claim 1, 2 or 3 wherein R⁴ substituents areselected from the group consisting of hydrogen, methyl, ethyl,iso-propyl, n-propyl, n-butyl, sec-butyl, iso-butyl, cyclopentyl,cyclohexyl, allyl, iso-but-2-enyl, 3-methylpentyl, —CH₂-cyclopropyl,—CH₂-cyclohexyl, —CH₂-indol-3-yl, phenyl, p-(phenyl)phenyl,m-(phenyl)phenyl o-fluorophenyl, m-fluorophenyl, p-fluorophenyl,p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl,m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl,m-trifluoromethylphenyl, p-(CH₃)₂NCH₂CH₂CH₂O-benzyl,p-(CH₃)₃COC(O)CH₂O-benzyl, p-phenylphenyl, 3,5-difluorophenyl,p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl, 4-(N-morpholino—CH₂CH₂O)-benzyl,—CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl, —CH₂-(3-tetrahydrofuranyl),—CH₂-thien-2-yl, —CH₂-thiazol-4-yl, —CH₂(1-methyl)cyclopropyl,—CH₂-thien-3-yl, thien-3-yl, thien-2-yl, —CH₂—C(O)O-t-butyl,—CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂, 2-methylcyclopentyl, -cyclohex-2-enyl,—CH[CH(CH₃)₂]COOCH₃, —(CH₂)₂SCH₃, —CH₂CH₂N(CH₃)₂, —CH₂C(CH₃)═CH₂,—CH₂CH═CHCH₃ (cis and trans), —CH₂OH, —CH(OH)CH₃, —CH(O-t-butyl)CH₃,—CH₂0CH₃, —(CH)₄NH-Boc, —(CH₂)₄NH₂, —(CH₂)₄N(CH₃)₂, —CH₂-pyridyl,pyridyl, —CH₂-naphthyl, —CH₂-(N-morpholino),p-(N-morpholino—CH₂CH₂0)-benzyl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzob]thiophen-2-yl, benzo[b]thiophen-3-yl,tetrazol-5-yl, 5-chlorobenzo b]thiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂-N-phthalimidyl, 2-methylthiazol-4-yl, andthieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl,5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-ethylphenyl,2-benzylphenyl, (4-ethylphenyl)phenyl, 4-tert-butylphenyl,4-n-butylphenyl, o-(4-chlorophenoxy)phenyl, furan-2-yl, and4-phenylacetylenylphenyl.
 24. The method according to claim 1, 2 or 3wherein Z is a covalent bond linking R¹ to —CX′X″— and R⁴ and R⁵ arefused to form a cycloalkyl group selected from the group consisting ofcyclopropyl and cyclobutyl.
 25. The method according to claims 1, 2 or 3wherein Z is a covalent bond linking R¹ to —CX′X″—, X is —C(O)Y and Y isselected from the group consisting of hydroxy, alkoxy or substitutedalkoxy.
 26. The method according to claim 25 wherein Y is alkoxy orsubstituted alkoxy selected from the group consisting of methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy,neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy,3-iodo-n-propoxy, 4-bromo-n-butoxy, —ONHC(O)OC(CH₃)₃, —ONHC(CH₃)₃ andhydroxy.
 27. The method according to claims 1, 2 or 3 wherein Z is acovalent bond linking R¹ to —CX′X″—, X is —C(O)Y and Y is —NR′R″. 28.The method according to claim 27 wherein Y is selected from the groupconsisting of amino (—NH₂), —NH(iso-butyl), —NH(sec-butyl),N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino,azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino,N-heptamethyleneimino, N-pyrrolidinyl, —NH-methallyl,—NHCH₂-(furan-2-yl), -NHCH₂-cyclopropyl, —NH(tert-butyl),—NH(p-methylphenyl), —NHOCH₃, —NHCH₂(p-fluorophenyl), —NHCH₂CH₂OCH₃,—NH-cyclopentyl, —NH-cyclohexyl, —NHCH₂CH₂N(CH₃)₂, —NHCH₂C(CH₃)₃,—NHCH₂-(pyrid-2-yl), —NHCH₂-(pyrid-3-yl), —NHCH₂-(pyrid-4-yl),N-thiazolindinyl, —N(CH₂CH₂CH₃)₂, —N[CH₂CH(CH₃)₂]₂, —NHOH, —NH(p-NO₂φ),—NHCH₂(p-NO₂φ), —NHCH₂(m-NO₂-φ), —N(CH₃)OCH₃, —N(CH₃)CH₂—φ,—NHCH₂-(3,5-di-fluorophenyl), —NHCH₂CH₂F, —NHCH₂(p—CH₃φ),—NHCH₂(m—CH₃Oφ), —NHCH₂(p—CF₃-φ, —N(CH₃)CH₂CH₂OCH₃, —NHCH₂CH₂φ,—NHCH(CH₃)φ, —NHCH₂-(p-F-φ), —N(CH₃)CH₂CH₂N(CH₃)₂,—NHCH₂-(tetrahydrofuran-2-yl), —NHCH₂(p-trifluoromethylphenyl),—NHCH₂C(CH₃)═CH₂, —NH—[(p-benzyl)pyrid-4-yl],—NH—[(2,6-dimethyl)pyrid-4-yl], —NH—(2-methylcyclohexyl),—NH—(4-methylcyclohexyl), —NH—[N-ethoxycarbonyl]-piperidin-4-yl, —NHOC(CH₃)₃, —NHCH₂CH₂CH₂CH₂φ, —C(O)NH(CH)₃O-(p—CH₃)φ, —C(O)NH(CH₂)₆NH₂,—NH—(tetrahydrofuran-2-yl), —N(CH₃)φ,—NH(CHD₄NHC(O)-(2-hydroxy-4-azido)-phenyl and —NH(CH₂)₆-(biotinamidyl).29. The method according to claims 1, 2 or 3 wherein X is —C(O)Y and Yis selected from the group consisting of —CH₂CH₂CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)CH₂CH₂CH(CH₃)₂, —CH(OH)O, —CH(OH)CH₂C(O)OCH₃, —C(OH)(CH₃)₂,—CH₂OCH₃, —CH₂OC(O)OCH₃, and —CH₂OC(O)C(CH₃)₃, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl,—CH₂CH₂CH(CH₃)₂, —CH₂-pyridy-2-yl, —CH₂-pyridy-3-yl, —CH₂-pyridy-4-yl,—CH₂-fur-2-yl, benzyl, cyclopentyl, phenyl, and —NH—SO₂—CH₃.
 30. Themethod according to claims 1, 2 or 3 wherein Z is a covalent bondlinking R¹ to —CX′X″—.
 31. The method according to claims 1, 2 or 3wherein the compound of formula I is selected from the group consistingof: N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidinemethyl esterN-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(3-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatetert-butyl ester N-[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methylester N-[N-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-[3-(N,N-dimethylamino)propoxy]phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalaninemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosinemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6(N,N-dimethylamino)hexanoatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-prolinemethyl ester1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2carboxylatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionatemethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(2-morpholinoethoxy)phenylalaninamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4-pyridyl)propionamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(2-pyridyl)propionamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol4-yl)propionatemethyl ester2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylatemethyl esterN-(3-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(1-naphthyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propionatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninebenzyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine3-bromopropyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-iodopropylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butylesterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-(3-pyridyl)acetamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N_(ε)-(tert-butoxycarbonyl)-L-lysinemethyl ester methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino4-phenylbutanoateN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-arnino-2-(4-pyridyl)acetamideN-[N-(phenylacetyl)-L-alaninyl]-L-threonine methyl esterN′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN′-[N-(phenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN′-[N-(phenylacetyl)-L-alaninyl)-L-valinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetateethyl ester N-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamideN-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamideN-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetateethyl ester N-[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methylester N-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxylatemethyl esterN-2-(N,N-dimethylamino)ethyl-N-methyl-N′[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl esterN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]glycine ethyl esterN-hydroxy-N′-[N-(3-nitrophenylacetyl)L-alaninyl]D,L-threoninamideN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propionatemethyl ester N-[N-( 3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine ethylester N-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl esterN-[N-[N-(isovaleryl)-L-valinyl]-L-phenylglycinyl]L-alanine iso-butylester N-[N-(isovaleryl)-L-phenylalaninyl]-L-alanine iso-butyl esterN-[N-(3,5-difuorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester1-[N-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2carboxyate ethylester N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-methoxy-N-methyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamideN-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN,N-di-n-propyl-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamideN-(4-nitrophenyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-iso-butyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-nitrophenyl)-N′-[N-rN-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamideN-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-benzyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(3,5-difluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(3-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl esterN-(4-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(phenylacetyl)-L-phenylglycinyl]-L-alanine ethyl esterN-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycinemethyl ester N-[N-(cyclohexylacetyl)-L-phenylglycinyl]-L-alanine ethylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methylesterN-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl-L-phenylglycinemethyl esterN-(2-phenylethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl-(S)-2-amino-3-cyclohexylpropionatemethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamideN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl esterN-(R)-α-methylbenzyl]-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[(S)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-fluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-trifluoromethylbenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(3,5-difuorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetateethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(isovaleryl)-2-amino-2-cyclohexylacetyl]-L-alanine ethyl esterN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-(2-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2amino2-(4-fluorophenyl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-(2-fluorophenyl)acetateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyln-L-alanineethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycineneopentyl esterN-tert-butyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyiglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine tert-butylester N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholineN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methylester4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl]morpholine4-[N-[N-(³-nitrophenylacetyl)-L-alaniinyl]-L-isoleucinyl]morpholineN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucineN-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine ethylester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoatemethyl ester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl esterN-2-methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methylester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methylesterN-(R)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide1-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidineN-(S)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl esterN-2-fluoroethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[(S)-6-methyl-3-oxohept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramideN-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetatemethyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)aetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl-(S)-2-amino-2-(2-thienyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetatetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticacid N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)acetate methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(methoxy-2-naphthyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl)acetatemethyl ester(3S,4S)-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-4-amino3-hydroxy-5-phenylpentanoatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoatemethyl ester N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylglycinetert-butyl esterN-tert-butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(4-phenylphenyl)acetamideN-[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycinetert-Butyl EsterN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butylester N-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methylester N-[N-(3,5difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycinemethyl ester N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methylester N-[N-(phenylacetyl)-L-alaninyl]-L-alanine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-leucine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-isoleucine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-proline methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-N_(ε)-(tert-butoxycarbonyl)-L-lysinemethyl ester N-[N-(phenylacetyl)-L-alaninyl]-glycine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-valine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanioate methyl esterN-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl esterN-[N-(3-nitrophenylacetyl) -L-alaninyl]-L-valineN-[N-(phenylacetyl)-L-alaninyl]-L-N-methylalanine methyl esterN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl esterN-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl esterN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproline ethylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylatemethyl esterN-[(S)-3-hydroxy-6-methylhept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenyl-α-fluoroacetyl)-L-alaniny]-L-phenylglycinetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycinemethyl esterN-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-2-methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN-[(S)-α-hydroxy-α-phenyl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-1,2-diphenylethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[Cα-hydroxy-α′-(4-hydroxyphenyl)-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-aianinyl]-L-phenylalaninamideN-[α-hydroxy-α′-pyrid-2-yl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-hydroxy-α′-pyrid-4-yl-iso-propyl]-N′-(3,5difluorophenylacetyl)-L-alaninamideN-[(S)-1-hydroxy-4-methylpent-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-methoxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-hydroxy-3-methyl-but-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)acetatemethyl ester N-[1-hydroxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-methoxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-methoxy-2-phenyl-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-acetoxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[2-hydroxy-1-(thien-2-yl)ethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalaninetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamideN-[N-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamide′N-[N-(n-caprotyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methylN-[N-(3, 5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine methylesterN-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylclycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenyglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl esterN-[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butylester N-[N-(cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl ester N-[N-(tert-butylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2-yl)glycinamideN-tert-butyl-N[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thicen-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothien-2-yl)glycinamideN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-phenyl)phenyglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamideN-(S)-(−)-α-methylbenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamideN-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)phenylglycinamideN-[N-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-L-phenylglycinetert-butyl esterN-tert-butyl-N′-[N-(3,5-difluorophenyl-α,α-difluoroacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-butylesterN-[(S)-1-oxo-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycinetert-butyl ester[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-butoxycarbonyl(hydroxyl amine) esterN-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidineN-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-cyclopropanemethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methoxy-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2-methylprop-2-enyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-(pyrid-3-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-(pyrid-4-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-furfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-cyclopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-1-benzylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2,2,6,6-tetramethylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-4-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-1-ethoxycarbonylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycineN-tert-butyl(hydroxylamine) esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazideN-(1-ethoxyethen-1-yl)-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinehydrazide N-[N-(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butylesterN-4-(phenyl)butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-3-(4-iodophenoxy)propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-6-(amino)hexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideHydrochlorideN-1-(phthalimido)pent-2-yl-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycinemethyl ester N-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-norleucineN-[N-(cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine tert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4fluorophenyfglycineiso-propyl ester N-(isopropyl)N′-[N-(3,5-difltiorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl esterN-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl esterN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine iso-butylester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methylester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-α-phenyl)prolinemethyl ester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazo4-yl)propionatetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamidetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-[N-(3 ,4-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(1-naphthylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(phenylacetyl-L-alaninyl]-D-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)acetamideN′-[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamideN′-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfonamideN″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamideN″-methyl-N″-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN″-4-fluorobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycineneopentyl esterN-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methylesterN″-4-methylphenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN″-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamideN-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-pentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideSN-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN-[1-phenyl-2-oxo-butan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-α-hydroxyphenylalaninemethyl esterN″-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinetert-butyl ester N′-N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycinetert-butyl ester[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline) methylesterN″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-n-butylphenylglycinamideN″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L4-(phenylacetenyl)phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D ,L-phenylglycinthioamideN-[1,3-diphenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-hexan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN″-n-hexyl-6-biotinamidyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamideN′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionineN′-[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methylester N″-tert-butylN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methylesterN-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycineN′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycinetert-butyl esterN′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycineN′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycinetert-butyl esterN-[2-hydroxy-1-(S)phenyleth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamideN-[2-hydroxyeth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycinetert-butyl ester[N-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester[N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester[N-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine methylester [N-(3-aminoproprionyl)-L-alaninyl]-L-phenylglycine tert-butylester; and[N-(3-tert-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycinetert-butyl ester.
 32. A pharmaceutical compositionn comprising apharmaceutically inert carrier and pharmaceutically effective amount ofa compound of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R² isselected from the group consisting of hydrogen, alky, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,aryl, heteroaryl and heterocyclic; each R³ is independently selectedfrom the group consisting of hydrogen and methyl and R³ together with R⁴can be fused to form a cyclic structure of from 3 to 8 atoms which isoptionally fused with an aryl or heteroaryl group; each R⁴ isindependently selected from the group consisting of hydrogen, alky,alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocyclic, substituted alkyl, substituted alkenyl and substitutedalkynyl; each R⁵ is selected from hydrogen and methyl or together withR⁴ forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selectedfrom the group consisting of —C(O)Y and —C(S)Y where Y is selected fromthe group consisting of (a) alkyl or cycloalkyl, (b) substituted alkylwith the proviso that the substitution on said substituted alkyl do notinclude ot-haloalkyl, ciiazoalkyl, α-OC(O)alkyl, or α-OC(O)aryl groups,(c) alkoxy or thioalkoxy, (d) substituted alkoxy or substitutedthioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)—NR′R″ where R′and R″ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substitutedalkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ orR″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclicgroup having from 2 to 8 carbon atoms optionally containing 1 to 2additional heteroatoms selected from oxygen, sulfur and nitrogen andoptionally substituted with one or more alkyl, alkoxy or carboxylalkylgroups, (j) —NHSO₂-R⁸ where R⁸ is selected from alkyl, substitutedaLkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic, (k) —NR⁹NR¹⁰R¹⁰ where R⁹ is hydrogen or alkyl, and eachR¹⁰ is independently selected from hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclic, and (l) —ONR⁹[C(O)O]_(z)R¹⁰ where z is zero or one, R⁹ andR¹⁰ are as defined above; X can also be —CR⁶R⁶Y′ where each R⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′is selected from the group consisting of hydroxyl, amino, thiol, alkoxy,substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R⁷, —SSR⁷,—SSC(O)R⁷ where R⁷ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X′ ishydrogen, hydroxy, or fluoro; X″ is hydrogen, hydroxy or fluoro, or X′and X″ together form an oxo group, Z is selected from the groupconsisting of a bond covalently lnking R¹ to —CX′X″—, oxygen and sulfur;S n is an integer equal to 1 or 2; and pharmaceutically acceptable saltsthereof with the provisos that: A. when R¹ is phenyl or 3-nitrophenyl,R² is methyl, R³ is hydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ andX″ are hydrogen, Z is a bond, and n is 1, then X is not —C(O)OH; B. whenR¹ is phenyl, R² is methyl, R³ is hydrogen, R⁴ is —CH(OH)CH₃ derivedfrom D-threonine, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond,and n is 1, then X is not —C(O)OH or —C(O)OCH₃; C. when R¹ is phenyl, R²is methyl, R⁴ is benzyl, R⁵ is hydrogen, X is methoxycarbonyl, X′ and X″are hydrogen, Z is a bond, and n is 1, then R³ is not methyl; D. when R¹is iso-propyl, R² is —CH₂C(O)NH₂, R³ is hydrogen, R⁴ is isobutyl, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—C(O)OCH₃; E. when R¹ is phenyl, R² is methyl, R⁵ is hydrogen, X is—C(O)OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R³, thenitrogen atom attached to R³, and R⁴ do not form1,2,3,4-tetrahydroisoquinolin-2-yl or pyrrolidin-2-yl; F. when R¹ isphenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is —C(O)OCH₃, X′and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ is not4-amino-n-butyl; G. when R¹ is 3-nitrophenyl, R² is methyl, R³ ishydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)NH₂ or —CH₂OH; H. when R¹ isphenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is —CH₂OCH₃, X′and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ is not benzyl orethyl; I. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is methyl, R⁴is S methyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and nis 1, then X is not —CHOHφ; J. when R¹ is 3,5-difluorophenyl, R² ismethyl, R³ is hydrogen, R⁴ is phenyl-derived from D-phenylglycine, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—CHOHφ or —CH₂OH; K. when R, is N-(2-pyrrolidinonyl), R₂ is methyl, R₃is hydrogen, R₄ is benzyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; L. when R¹ is3,5-difluorophenyl, R¹ is methyl derived from D-alanine, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl; M. whenR¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is hydrogen,R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then Xis not —CH₂OH; N. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ ishydrogen, R⁴ is 4-phenylphenyl, R⁵ is hydrogen, X′ and X″ are hydrogen,Z is a bond, and n is 1, then X is not —C(O)NHC(CH)₃; and O. when R¹ is3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is phenyl derivedfrom D-phenylglycine, R¹ is hydrogen, X′ and X″ are hydrogen, Z is abond, and n is 1, then X is not —C(O)NHCH(CH₃)φ.
 33. The pharmaceuticalcomposition according to claim 32 wherein R¹ is an unsubstituted arylgroup and Z is a bond covalently linking R¹ to —CX′X″—.
 34. Thepharmaceutical composition according to claim 33 wherein theunsubstituted R¹ aryl group is selected from the group consisting ofphenyl, 1-naphthyl and 2-naphthyl.
 35. The pharmaceutical compositionaccording to claim 32 wherein R¹ is a substituted aryl group and Z is abond covalently linking R¹ to —CX′X″—.
 36. The pharmaceuticalcomposition according to claim 35 wherein said substituted aryl group isa mono-substituted, di-substituted or tri-substituted phenyl group. 37.The pharmaceutical composition according to claim 36 wherein thesubstituted phenyl groups are selected from the group consisting of4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl,4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl,3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl,3-trifluoromethylphenyl, 2-hydroxy-phenyl, 2-methylphenyl,2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 3 ,4-dibromophenyl, 3,4-dichlorophenyl,3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl,2,4-dichlorophenyl, and 2,5-difluorophenyl.
 38. The pharmaceuticalcomposition according to claim 32 wherein R¹ is an alkaryl group and Zis a bond covalently linking R¹ to —CX′X″—.
 39. The pharmaceuticalcomposition according to claim 38 wherein the R¹ alkaryl group isselected from the group consisting of benzyl, 2-phenylethyl, and3-phenyl-n-propyl.
 40. The pharmaceutical composition according to claim32 wherein R¹ is selected from the group consisting of alkyl, alkenyl,cycloalkyl and cycloalkenyl groups and Z is a bond covalently linking R¹to —CX′X″—.
 41. The pharmaceutical composition according to claim 40wherein R¹ is alky.
 42. The pharmaceutical composition according toclaim 40 wherein R¹ is cycloalkyl.
 43. The pharmaceutical compositionaccording to claim 40 wherein R¹ is alkenyl.
 44. The pharmaceuticalcomposition according to claim 40 wherein R¹ is cycloalkenyl.
 45. Thepharmaceutical composition according to claim 40 wherein the R¹ alkyl,cycloalkyl, alkenyl and cycloalkenyl groups are selected from the groupconsisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, —CH₂CH=CH₂, —CH₂CH═CH(CH₂)₄CH₃, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, cyclohex-1-enyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, —CH₂-cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl,aminomethyl, and N-tert-butoxycarbonylaminomethyl.
 46. Thepharmaceutical composition according to claim 32 wherein R¹ is selectedfrom the group consisting of heteroaryl and substituted heteroarylgroups and Z is a bond covalently linking R¹ to —CX′X″—.
 47. Thepharmaceutical composition according to claim 46 wherein the R¹heteroaryl and substituted heteroaryl groups are selected from the groupconsisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls(including 5-fluoropyrid-3-yl), chloropyridyls (including5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl,2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl,2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl,2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl.
 48. The pharmaceuticalcomposition according to claim 32 wherein R² is selected from the groupconsisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl andheterocyclic.
 49. The pharmaceutical composition according to claim 48wherein R² is selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl,4-fluorophenyl, 3,5-difluoro-phenyl, 4-methoxyphenyl, benzyl,cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl,thien-3-yl, —CH₂CH₂SCH₃, —CH₂OCH₂O, —CH(CH₃)OCH₂φ, —CH(OH)CH₃ and —CHOH.50. The pharmaceutical composition according to claim 32 wherein X′ andX″ are hydrogen and Z is a bond covalently linking R¹ to —CX′X″—. 51.The pharmaceutical composition according to claim 50 wherein R³ isselected from the group consisting of hydrogen, methyl or together withR⁴ and the nitrogen to which R³ is attached forms pyrrolidin-2-yl,2,3-dihydroindol-2-yl, piperidin-2-yl, 4-hydroxy-pyrrolidin-2-yl and1,2,3,4- tetrahydroisoquinolin-3-yl.
 52. The pharmaceutical compositionaccording to claim 32 wherein R⁴ substituents are selected from thegroup consisting of hydrogen, methyl, ethyl, iso-propyl, n-propyl,n-butyl, sec-butyl, iso-butyl, cyclopentyl, cyclohexyl, allyl,iso-but-2-enyl, 3-methylpentyl, —CH₂-cyclopropyl, —CH2—Cyclohexyl,—CH₂-indol-3-yl, phenyl, p-(phenyl)phenyl, m-(phenyl)phenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl,m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl,p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl,p-(CH₃)₂NCH₂CH₂CH₂O-benzyl, p-(CH₃)₃COC(O)CH₂O-benzyl, p-phenylphenyl,3,5-difluorophenyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,4-(N-morpholino—CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thien-2-yl, —CH₂-thiazol-4-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thien-3-yl, thien-3-yl, thien-2-yl,—CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂, 2-methylcyclopentyl,-cyclohex-2-enyl, —CH [CH(CH₃)]COOCH₃, —(CH₂)₂SCH₃, —CH₂CH₂N(CH₃)₂,—CH₂C(CH₃)=CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH, —CH(OH)CH₃,—CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH)₄NH-Boc, -(CH2)₄NH₂, -(CH₂)₄N(CH₃)₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂-(N-morpholino),p-(N-morpholino—CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzob]thiophen-2-yl, benzo[b]thiophen-3-yl,tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂-N-phthalimidyl, 2-methylthiazol-4-yl, andthieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl,5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-ethylphenyl,2-benzylphenyl, (4-ethylphenyl)phenyl, 4-tert-butylphenyl,4-n-butylphenyl, o-(4-chlorophenoxy)phenyl, furan-2-yl, and4-phenylacetylenylphenyl.
 53. The pharmaceutical composition accordingto claim 32 wherein Z is a covalent bond linking R¹ to —CX′X″— and R⁴and R⁵ are fused to form a cycloalkyl group selected from the groupconsisting of cyclopropyl and cyclobutyl.
 54. The pharmaceuticalcomposition according to claim 32 wherein Z is a covalent bond linkingR¹ to —CX′X″—, X is —C(O)Y and Y is selected from the group consistingof hydroxy, alkoxy or substituted alkoxy.
 55. The pharmaceuticalcomposition according to claim 54 wherein Y is alkoxy or substitutedalkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, neo pentoxy, benzyloxy,2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4 bromo-n-butoxy,—ONHC(O)OC(CH₃)₃, —ONHC(CH₃)₃ and hydroxy.
 56. The pharmaceuticalcomposition according to claim 32 wherein Z is a covalent bond linkingR′ to —CX′X″—, X is —C(O)Y and Y is —NR′R″.
 57. The pharmaceuticalcomposition according to claim 56 wherein Y is selected from the groupconsisting of amino (—NH), —NH(iso-butyl), —NH(sec-butyl),N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino,azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino,N-heptamethylene-imino, N-pyrrolidinyl, —NH—methallyl,—NHCH₂-(furan-2-yl), —NHCH₂-cyclopropyl, —NH(tert-butyl), —NH(pmethylphenyl), —NHOCH₃, —NHCH₂(p-fluorophenyl), —NHCH₂CH₂OCH₃,—NH—cyclopentyl, —NH-cyclohexyl, —NHCH₂CH₂N(CH₃)₂, —NHCH₂C(CH₃)₃,—NHCH₂-(pyrid-2-yl), —NHCH₂-(pyrid-3-yl), —NHCH₂-(pyrid-4-yl),N-thiazolindinyl, —N(CH₂CH₂CH₃)₂, —N[CH₂CH(CH3)]₂, —NHOH, —NH(p-NO₂φ),—NHCH₂p-NO₂-φ, —NHCH₂(m-NO₂-φ, —N(CH₃)OCH₃, —N(CH₃)CH₂—φ,—NHCH₂-(3,5difluorophenyl), —NHCH₂CH₂F, —NHCH₂(p—CH₃φ),—NHCH₂(m—CH₃O—φ), —NHCH₂(p—CF₃φ), —N(CH₃)CH₂CH₂0CH₃, —NHCH₂CH₂φ,—NHCH(CH₃)φ, —NHCH₂-p-F-φ), —N(CH₃)CH₂CH₂N(CH₃)₂,—NHCH₂-(tetrahydrofuran-2-yl), —NHCH₂(p-trifluoromethylphenyl),—NHCH₂C(CH₃)═CH₂, —NH—[(p-benzyl)pyrid-4-yl],—NH—[(2,6-dimethyl)pyrid-4-yl], —NH—(2-methylcyclohexyl),—NH—(4-methylcyclohexyl), —NH—[N-ethoxycarbonyl]-piperidin-4-yl,—NHOC(CH₃)₃, —NHCH₂CH₂CH₂CH₂—φ, —C(O)NH(CH₂)₃O-(P—CH₃)φ,—C(O)NH(CH₂)₆NH₂, —NH—(tetrahydrofuran-2-yl), —N(CH₃)φ,—NH(CH₂)₄NHC(O)-(2-hydroxy-4-azido)-phenyl and —NH(CH₂)₆-(biotinamidyl).58. The pharrnaceutical composition according to claim 32 wherein X is—C(O)Y and Y is selected from the group consisting of—CH₂CH₂CH₂CH(CH₃)₂, —CH₂OH, —CH(OH)CH₂CH₂CH(CH₃)₂, —CH(OH)φ,—CH(OH)CH₂C(O)OCH₃, —C(OH)(CH₃)₂, —CH₂0CH₃, —CH₂OC(O)OCH₃, and—CH₂OC(O)C(CH₃)₃, methyl, ethyl, iso-propyl, n-propyl, iso-butyl,n-butyl, sec-butyl, tert-butyl, —CH₂CH₂CH(CH₃)₂, —CH₂-pyridy-2-yl,—CH₂-pyridy-3-yl, —CH₂-pyridy-4-yl, —CH₂-fur-2-yl, benzyl, cyclopentyl,phenyl, and —NH—SO₂—CH₃.
 59. The pharmaceutical composition according toclaim 32 wherein Z is a covalent bond linking R¹ to —CX′X″—.
 60. Thepharmaceutical composition according to claim 32 wherein the compound offormula I is selected from the group consisting of:N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methylesterN-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(3-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatetert-butyl ester N-[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methylester N-[N-(dec-4-enoyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)propoxy]phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalaninemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylamino)hexanoatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-prolinemethyl ester1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2carboxylatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(4-pyridyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionatemethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4-pyridyl)propionamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(2-pyridyl)propionamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol4-yl)propionatemethyl ester2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylatemethyl esterN-(3-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(1-naphthyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(2-thienyl)propionatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninehenzyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine3-bromo propyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-iodopropylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butylesterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-(2-pyridyl)acetamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N,-(tert-butbxycarbonyl)-L-lysinemethyl ester methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoateN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine-2-phenylethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetamideN-[N-(phenylacetyl)-L-alaninyl]-L-threonine methyl esterN′-[N-phenylacetyl)-L-alaninyl]-L-leucinamideN′-[N-(phenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN′-[N-(phenylacetyl)-L-alaninyl)-L-valinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amnino-2-(3-pyridyl)acetateethyl ester N-methyl-N ′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamideN-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN-meth-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamideN-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl-(S)-2-aminohexanamideN,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetateethyl ester N-[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methylester N-[N-(cyclopentylacetyl)-L-a.aninyl]Lphenylalanine methyl esterN-[N-(cyclohex-t-enylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-arninocyclopropane-1-carboxylatemethyl esterN-2-(N,N-dimethylamino)ethyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(cyclopropylacetyl)-L-alaninyl]Lphenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl esterN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]glycine ethyl esterN-hydroxy-N′-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamideN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propionatemethyl ester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine ethylester N-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl esterN-[N-[N-(isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanine isobutylester N-[N-(isovaleryl)-L-phenylalaninyl]-L-alanine isobutyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester1-[N-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2-carboxylate ethylester N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-methoxy-N-methyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamideN-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN,N-di-n-propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamideN-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[′,N′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamdeN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylaianine methyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-iso-butyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-nitrophenyl)-N′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamrideN-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-benzyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(3,5difluorobenzyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(3-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl esterN-(4-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(phenylacetyl)-L-phenylglycinyl]-L-alanine ethyl esterN-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycinemethyl ester N-[N-(cyclohexylacetyl)-L-phenylglycinyl]-L-alanine ethylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methylesterN-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-phenylglycinemethyl esterN-(2-phenylethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionatemethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamideN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl esterN-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[(S)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-fluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-trifluoromethylbenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaniyl]-L-alaninanideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetateethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(isovaleryl)-2amino-2-cyclohexylacetyl]-L-alanine ethyl esterN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-(2-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)acetateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanineethyl esterN-[N-(3,5difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionateethyl ester N-[N-(3,5difluorophenylacetyl)-L-alaninyl]-L-phenylglycineneopentyl esterN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine tert-butylester N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholineN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methylester4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl]morpholine4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholineN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucineN-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine ethylester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoatemethyl ester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl esterN-2-methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-2-pyridylmethyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methylester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methylesterN-(R)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide1-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidineN-(S)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl esterN-2-fluoroethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[(S)-6-methyl-3-oxohept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramideN-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetatemethyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamideN-[N-(3,5-dfluorophenylacetyl)-L-alaninyl]-2-anino-2-(5-chlorobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiphen-3-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)aetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetatemethyl ester1N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-anino-2-(2-thienyl)acetatetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticacidN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(6methoxy-2-naphthyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-aino-2-(2-metyltiazol-4-yl)acetatemethyl ester (3S,4S)-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]4-amino-3-hydroxy-5-phenylpentanoatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoatemethyl ester N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylglycinetert-butyl esterN-tert-butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amiino2-(4-phenylphenyl)acetamideN-[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl-L-phenylglycinetert-Butyl EsterN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butylester N-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycinemethyl ester N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methylester N-[N-(phenylacetyl)-L-alaninyl]-L-alanine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-leucine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-isoleucine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-proline methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-N,-(tert-butoxycarbonyt)-L-lysine methylester N-[N-(phenylacetyl)-L-alaninyl]-glycine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-valine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl esterN-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valineN-[N-(phenylacetyl)-L-alaninyl]-L-N-methylalanine methyl esterN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine iso-butyl esterN-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl esterN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproline ethylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2 carboxylatemethyl esterN-[(S)-3-hydroxy-6-methylhept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-l-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenyl-α-fluoroacetyl)-L-alaniny]-L-phenylglycinetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycinemethyl esterN-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-2-methoxyethyl-N′-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN-[(S)-α-hydroxy-α-phenyl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-1,2-diphenylethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-hydroxy-α′-(4-hydroxyphenyl)-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[α-hydroxy-α′-pyrid-2-yl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-hydroxy-α′-pyrid-4-yl-iso-propyl]-N′-(3,5difuorophenylacetyl)-L-alaninamideN-[(S)-1-hydroxy-4-methylpent-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-methoxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-hydroxy-3-methyl-but-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)acetatemethyl esterN-[1-hydroxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-methoxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-methoxy-2-phenyl-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-acetoxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N′-(3,5difluorophenylacetyl)-L-alaninamideN-[2-hydroxy-1-(thien-2-yl)ethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalaninetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamideN-[N-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(n-caprotyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl esterN-[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butylester N-[N-(cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl ester N-[N-(tert-butylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothien-2-yl)glycinamideN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamideN-(S)-(−)-α-methylbenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(ethyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(cyclohexyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamideN-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(phenyl)phenylglycinamideN-[N-(3,5-difluorophenyl-o-hydroxyacetyl)-L-alaninyl]-L-phenylglycinetert-butyl esterN-tert-butyl-N′-[N-(3,5-difluorophenyl-α,α-difluoroacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-butylesterN-[(S)-1-oxo-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycinetert-butyl ester[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyllmorpholineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-butoxycarbonyl(hydroxyl amine) esterN-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidineN-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-cyclopropanemethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methoxy-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2-methylprop-2-enyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-(pyrid-3-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-(pyrid-4-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-furfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-cyclopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenyIglycinamideN-1-benzylpiperidin-4-yl-N[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2,2,6,6-tetramethylpiperidin-4-yl-N′-[N(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-4-methylcyclohexyl-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-1-ethoxycarbonylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-butyl(hydroxylamine) esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazideN-(1-ethoxyethen-1-yl)-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinehydrazide N-[N-(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butylesterN-4-(phenyl)butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-3-(4-iodophenoxy)propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-6-(amino)hexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideHydrochlorideN-1-(phthalimido)pent-2-yl-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycinemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucineN-[N-(cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine tert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycineiso-propyl ester N-(isopropyl)N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl esterN-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl esterN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine isobutylester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methylester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-α-phenyl)prolinemethyl ester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(5-chlorobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol4-yl)propionatetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamidetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-[N-(3 ,4-dichlorophenytacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-chlorophenylacetyl)-L-alaniny]D-phenylglycinamideN-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-methylphenylacetyl)-L-alaninyllD-phenyllycinamideN-[N-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-methoxyphenytacetyl)-L-alaninyl]-D-pbenylglycinamideN-[N-(2-chlorophenylcetyl)-L-alaiinyl]- D-phenylglycinaaide N-[N-(-naphthylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(2-naphthylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-²-(²-furanyl)acetamideN′-[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamideN′-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfonamideN″-methyl-N′-phenyl-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-glycinamideN′-methyl-N′-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamideN′-methyl-N″-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN″-4-fluorobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycineneopentyl esterN-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl)-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methylesterN″-4-methylphenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN″-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamideN′-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamideN-[N-(3, 5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamideN-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-pentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN-[1-phenyl-2-oxo-butan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-α-hydroxyphenylalaninemethyl esterN″-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycinetert-butyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycinetert-butyl ester [N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline) methyl esterN″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-n-butylphenylglycinamideN″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylacetenyl)phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamideN-[1, 3-diphenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-hexan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN″-n-hexyl-6-biotinamidyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamideN′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionineN′-[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methylester N″-tert-butylN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methylester N-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycineN′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycinetert-butyl esterN′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycineN′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycinetert-butyl esterN-[2-hydroxy-1-(S)phenyleth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamideN-[2-hydroxyeth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycinetert-butyl esterN-(2,5-dichlorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester[N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester[N-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine methylester [N-(3-aminoproprionyl-L-alaninyl)-L-phenylglycine tert-butylester; and[N-(3-tert-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycinetert-butyl ester.
 61. A compound of formula I:

wherein R¹ is selected from the group consisting of alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substitutedalkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; R² isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, aryl, heteroaryl and heterocyclic; each R³ is independentlyselected from the group consisting of hydrogen and methyl and R³together with R⁴ can be fused to form a cyclic structure of from 3 to 8atoms which is optionally fused with an aryl or heteroaryl group; eachR⁴ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl,heterocyclic, substituted alkyl, substituted alkenyl and substitutedalkynyl; each R⁵ is selected from hydrogen and methyl or together withR⁴ forms a cycloalkyl group of from 3 to 6 carbon atoms; X is selectedfrom the group consisting of —C(O)Y and —C(S)Y where Y is selected fromthe group consisting of (a) alkyl or cycloalkyl, (b) substituted alkylwith the proviso that the substitution on said substituted alkyl do notinclude α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl, or α—OC(O)aryl groups,(c) alkoxy or thioalkoxy, (d) substituted alkoxy or substitutedthioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substitutedalkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of R′ orR″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclicgroup having from 2 to 8 carbon atoms optionally containing 1 to 2additional heteroatoms selected from oxygen, sulfur and nitrogen andoptionally substituted with one or more alkyl, alkoxy or carboxylalkylgroups, (j) —NHSO₂—R⁸ where R⁸ is selected from alkyl, substitutedalkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl andheterocyclic, (k) —NR⁹NR¹⁰R¹⁰ where R⁹ is hydrogen or alkyl, and eachR¹⁰ is independently selected from hydrogen, alky, substituted alky,alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl,heterocyclic, and (l) —ONR⁹[C(O)O]_(z)R¹⁰ where z is zero or one, R⁹ andR¹⁰ are as defined above; X can also be —CR⁶R⁶Y′ where each R⁶ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y′is selected from the group consisting of hydroxyl, amino, thiol, alkoxy,substituted alkoxy, thioalkoxy, substituted thioalkoxy, —OC(O)R⁷, —SSR⁷,—SSC(O)R⁷ where R⁷ is selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, X′ ishydrogen, hydroxy, or fluoro; X″ is hydrogen, hydroxy or fluoro, or X′and X″ together form an oxo group, Z is selected from the groupconsisting of a bond covalently linking R¹ to —CX′X″-, oxygen andsulfur; n is an integer equal to 1 or 2; and pharmaceutically acceptablesalts thereof with the provisos that: A. when R¹ is phenyl or3-nitrophenyl, R² is methyl, R³ is hydrogen, R⁴ is —CH(OH)CH₃, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—C(O)OH; B. when R¹ is phenyl, R² is methyl, R³ is hydrogen, R⁴ is—CH(OH)CH₃ derived from D-threonine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)OH or —C(O)OCH₃;C. when R¹ is phenyl, R² is methyl, R⁴ is benzyl, R⁵ is hydrogen, X ismethoxycarbonyl, X′ and X″ are hydrogen, Z is a bond, and n is 1, thenR³ is not methyl; D. when R¹ is iso-propyl, R² is —CH₂C(O)NH₂, R³ ishydrogen, R⁴ is iso-butyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; E. when R¹ is phenyl, R² ismethyl, R⁵ is hydrogen, X is —C(O)OCH₃, X′ and X″ are hydrogen, Z is abond, and n is 1, then R³, the nitrogen atom attached to R³, and R⁴ donot form 1,2,3,4-tetrahydroisoquinolin-2-yl or pyrrolidin-2-yl; F. whenR¹ is phenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is—C(O)OCH₃, X′ and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ isnot 4-amino-n-butyl; G. when R¹ is 3-nitrophenyl, R² is methyl, R³ ishydrogen, R⁴ is —CH(OH)CH₃, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)NH₂ or —CH₂OH; H. when R¹ isphenyl, R² is methyl, R³ is hydrogen, R⁵ is hydrogen, X is —CH20CH₃, X′and X″ are hydrogen, Z is a bond, and n is 1, then R⁴ is not benzyl orethyl; I. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ is methyl, R⁴is methyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is1, then X is not —CHOHφ; J. when R¹ is 3,5-difluorophenyl, R² is methyl,R³ is hydrogen, R⁴ is phenyl derived from D-phenylglycine, R⁵ ishydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then X is not—CHOHO or —CH₂OH; K. when R₁ is N-(2-pyrrolidinonyl), R¹ is methyl, R₃is hydrogen, R₄ is benzyl, R⁵ is hydrogen, X′ and X″ are hydrogen, Z isa bond, and n is 1, then X is not —C(O)OCH₃; L. when R¹ is3,5-difluorophenyl, R² is methyl derived from D-alanine, R³ is hydrogen,R⁴ is phenyl derived from D-phenylglycine, R⁵ is hydrogen, X′ and X″ arehydrogen, Z is a bond, and n is 1, then X is not —C(O)NH-benzyl; M. whenR¹ is 3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is hydrogen,R⁵ is hydrogen, X′ and X″ are hydrogen, Z is a bond, and n is 1, then Xis not —CH₂OH; N. when R¹ is 3,5-difluorophenyl, R² is methyl, R³ ishydrogen, R⁴ is 4-phenylphenyl, R⁵ is hydrogen, X′ and X″ are hydrogen,Z is a bond, and n is 1, then X is not —C(O)NHC(CH)₃; and O. when R¹ is3,5-difluorophenyl, R² is methyl, R³ is hydrogen, R⁴ is phenyl derivedfrom D-phenylglycine, R⁵ is hydrogen, X′ and X″ are hydrogen, Z is abond, and n is 1, then X is not —C(O)NHCH(CH₃)φ.
 62. The compoundaccording to claim 61 wherein R¹ is an unsubstituted aryl group and Z isa bond covalently linking R¹ to —CX′X″—.
 63. The compound according toclaim 62 wherein the unsubstituted R¹ aryl group is selected from thegroup consisting of phenyl, 1-naphthyl and 2-naphthyl.
 64. The compoundaccording to claim 61 wherein R¹ is a substituted aryl group and Z is abond covalently linking R¹ to —CX′X″—.
 65. The compound according toclaim 64 wherein said substituted aryl group is a mono-substituted,di-substituted or tri-substituted phenyl group.
 66. The compoundaccording to claim 65 wherein the substituted phenyl groups are selectedfrom the group consisting of 4-fluorophenyl, 4-chlorophenyl,4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl,3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl,3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl,2-hydroxy-phenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl,3,4-difluorophenyl, 2,3,4,5, 6-pentafluorophenyl, 3, 4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylene-dioxyphenyl, 3,5-difluorophenyl,3,5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-difluorophenyl.
 67. Thecompound according to claim 61 wherein R¹ is an alkaryl group and Z is abond covalently linking R¹ to —CX′X″—.
 68. The compound according toclaim 67 wherein the R¹ alkaryl group is selected from the groupconsisting of benzyl, 2-phenylethyl, and 3-phenyl-n-propyl.
 69. Thecompound according to claim 61 wherein R¹ is selected from the groupconsisting of alkyl, alkenyl, cycloalkyl and cycloalkenyl groups and Zis a bond covalently linking R¹ to —CX′X″—.
 70. The compound accordingto claim 69 wherein R¹ is alkyl.
 71. The compound according to claim 69wherein R¹ is cycloalkyl.
 72. The compound according to claim 69 whereinR¹ is alkenyl.
 73. The compound according to claim 69 wherein R¹ iscycloalkenyl.
 74. The compound according to claim 69 wherein the R¹alkyl, cycloalkl, alkenyl and cycloalkenyl groups are selected from thegroup consisting of iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, —CH₂CH═CH₂, —CH₂CH═CH(CH₂)₄CH₃, cyclopropyl, cyclobutyl,cyclohexyl, cyclopentyl, cyclohex-1-enyl, —CH₂cyclopropyl,—CH₂-cyclobutyl, —CH₂cyclohexyl, —CH₂-cyclopentyl, —CH₂CH₂-cyclopropyl,—CH₂CH₂-cyclobutyl, —CH₂CH₂-cyclohexyl, —CH₂CH₂-cyclopentyl,aminomethyl, and N-tert-butoxycarbonylaminomethyl.
 75. The compoundaccording to claim 61 wherein R¹ is selected from the group consistingof heteroaryl and substituted heteroaryl groups and Z is a bondcovalenthy linking R¹ to —CX′X″—.
 76. The compound according to claim 75wherein the R¹ heteroaryl and substituted heteroaryl groups are selectedfrom the group consisting of pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, 5 benzothiazol-4-yl,2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl,2-chlorothiophen-5-yl, 3-methylisoxazo1-5-yl,2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl.
 77. The compoundaccording to claim 61 wherein R² is selected from the group consistingof alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl andheterocyclic.
 78. The compound according to claim 77 wherein R² isselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, isobutyl, sec-butyl, phenyl, 4-fluorophenyl,3,5-difluoro-phenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl,cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, —CH₂CH₂SCH₃,—CH₂OCH₂+, —CH(CH₃)OCH₂O, —CH(OH)CH₃ and —CH₂OH.
 79. The compoundaccording to claim 61 wherein X′ and X″ are hydrogen and Z is a bondcovalently linking R¹ to —CX′X″—.
 80. The compound according to claim 79wherein R³ is selected from the group consisting of hydrogen, methyl ortogether with R⁴ and the nitrogen to which R³ is attached formspyrrolidin-2-yl, 2,3-dihydroindol-2-yl, piperidin-2-yl,4-hydroxy-pyrrolidin-2-yl and 1,2,3,4-tetrahydroisoquinolin-3-yl. 81.The compound according to claim 61 wherein R⁴ substituents are selectedfrom the group consisting of hydrogen, methyl, ethyl, iso-propyl,n-propyl, n-butyl, sec-butyl, iso-butyl, cyclopentyl, cyclohexyl, allyl,iso-but-2-enyl, 3-methylpentyl, —CH₂-cyclopropyl, —CH₂-cyclohexyl,—CH₂-indol-3-yl, phenyl, p-(phenyl)phenyl, m-(phenyl)phenyl,o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl,m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl,p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl,p-(CH₃)₂NCH₂CH₂CH₂O-benzyl, p-(CH₃)₃COC(O)CH₂O-benzyl, p-phenylphenyl,3,5-difluorophenyl, p-(HOOCCH₂O)-benzyl, 2-aminopyrid-6-yl,4-(N-morpholino—CH₂CH₂O)-benzyl, —CH₂CH₂C(O)NH₂, —CH₂-imidazol-4-yl,—CH₂-(3-tetrahydrofuranyl), —CH₂-thien-2-yl, —CH₂-thiazol-4-yl,—CH₂(1-methyl)cyclopropyl, —CH₂-thien-3-yl, thien-3-yl, thien-2-yl,—CH₂—C(O)O-t-butyl, —CH₂—C(CH₃)₃, —CH₂CH(CH₂CH₃)₂, 2-methylcyclopentyl,-cyclohex-2-enyl, —CH[CH(CH₃)2]COOCH₃, —(CH)SCH₃, —CH₂CH₂N(CH₃)₂,—CH₂C(CH₃)═CH₂, —CH₂CH═CHCH₃ (cis and trans), —CH₂OH, —CH(OH)CH₃,—CH(O-t-butyl)CH₃, —CH₂OCH₃, —(CH)₄NH-Boc, —(CH₂)₄NH₂, —(CH₂)₄N(CH₃)₂,—CH₂-pyridyl, pyridyl, —CH₂-naphthyl, —CH₂—(N-morpholino),p-(N-morpholino—CH₂CH₂O)-benzyl, benzo[b]thiophen-2-yl,benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl,4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl,tetrazol-5-yl, 5-chlorobenzoblthiophen-3-yl, benzo[b]thiophen-5-yl,6-methoxynaphth-2-yl, —CH₂-N-phthalimidyl, 2-methylthiazol-4-yl, andthieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl,5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-ethylphenyl,2-benzylphenyl, (4-ethylphenyl)phenyl, 4-tert-butylphenyl,4-n-butylphenyl, o-(4-chlorophenoxy)phenyl, furan-2-yl, and4-phenylacetylenylphenyl.
 82. The compound according to claim 61 whereinZ is a covalent bond linking R¹ to —CX′X″— and R⁴ and R⁵ are fused toform a cycloalkyl group selected from the group consisting ofcyclopropyl and cyclobutyl.
 83. The compound according to claim 61wherein Z is a covalent bond linking R¹ to —CX′X″—, X is —C(O)Y and Y isselected from the group consisting of hydroxy, alkoxy or substitutedalkoxy.
 84. The compound according to claim 83 wherein Y is alkoxy orsubstituted alkoxy selected from the group consisting of methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, tert-butoxy,neopentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy,3-iodon-propoxy, 4-bromon- butoxy, —ONHC(O)OC(CH₃)₃, —ONHC(CH₃)₃ andhydroxy.
 85. The compound according to claim 61 wherein Z is a covalentbond linking R¹ to —CX′X″—, X is —C(O)Y and Y is —NR′R″.
 86. Thecompound according to claim 85 wherein Y is selected from the groupconsisting of amino (—NH), —NH(iso-butyl), —NH(sec-butyl),N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino,azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino,N-heptamethylene-imino, N-pyrrolidinyl, —NH-methallyl,—NHCH₂-(furan-2-yl), —NHCH₂-cyclopropyl, —NH(tert-butyl),—NH(p-methylphenyl), —NHOCH₃, —NHCH₂(p-fluorophenyl), —NHCH₂CH₂OCH₃,—NH-cyclopentyl, —NH-cyclohexyl, —NHCH₂CH₂N(CH₃)₂, —NHCH₂C(CH₃)₃,—NHCH₂-(pyrid-2-yl), —NHCH₂-(pyrid-3-yl), —NHCH₂-(pyrid-4-yl),N-thiazolindinyl, —N(CH₂CH₂CH₃)₂, —N[CH₂CH(CH₃)21₂, —NHOH, —NH(p-NO₂-φ),—NHCH₂—NO₂-φ, —NHCH₂(m—NO₂-φ), —N(CH₃)OCH₃,—N(CH₃)CH₂-φ,—NHCH₂-(3,5difluorophenyl), —NHCH₂CH₂F, —NHCH₂(p—CH₃-φ),—NHCH₂(m—CH₃O-φ), —NHCH₂(p—CF₃-φ), —N(CH₃)CH₂CH₂0CH₃, —NHCH₂CH₂+,—NHCH(CH₃)0, —NHCH₂—p-F-φ), —N(CH₃)CH₂CH₂N(CH₃)₂,—NHCH₂-(tetrahydrofuran-2-yl), —NHCH₂(P-trifluoromethylphenyl),—NHCH₂C(CH₃)=CH₂, —NH—[(p-benzyl)pyrid-4-yl], —NH—[(2,6-dimethyl)pyrid-4-yl], —NH—(2-methylcyclohexyl),—NH—(4-methylcyclohexyl), —NH—[N-ethoxycarbonyl]-piperidin-4-yl,—NHOC(CH₃)₃, —NHCH₂CH₂CH₂CH₂-φ, —C(O)NH(CH₂)₃O-(p-CH₃)φ,—C(O)NH(CH)₆NH₂, —NH—(tetrahydrofuran-2-yl), —N(CH₃)φ,—NH(CH₂)₄NHC(O)—(2-hydroxy4-azido)-phenyl and -NH(CH,)₆-(biotinamidyl).87. The compound according to claim 61 wherein X is —C(O)Y and Y isselected from the group consisting of —CH₂CH₂CH₂CH(CH₃)₂, —CH₂OH,—CH(OH)CH₂CH₂CH(CH₃)₂, —CH(OH)φ, —CH(OH)CH₂C(O)OCH₃, —C(OH)(CH₃)₂,—CH₂OCH₃, —CH₂OC(O)OCH₃, and —CH₂OC(O)C(CH₃)₃, methyl; ethyl,iso-propyl, n-propyl, isobutyl, n-butyl, sec-butyl, tert-butyl,—CH₂CH₂CH(CH₃)₂, —CH₂-pyridy-2-yl, —CH₂-pyridy-3-yl, —CH₂-pyridy-4-yl,—CH₂-fur-2-yl, benzyl, cyclopentyl, phenyl, and —NH—SO₂—CH₃.
 88. Thecompound according to claim 61 wherein Z is a covalent bond linking R¹to —CX′X″—.
 89. The compound according to claim 61 wherein the compoundof formula I is selected from the group consisting of:N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methylesterN-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(3-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-pyridyl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoatetert-butyl ester N-[N-(pent-4-enoyl)-L-alaninyl]-L-phenylalanine methylester N-[N-(dec4-enoyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)propoxy]phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalaninemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylamino)hexanoatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-prolinemethyl ester1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionatemethyl esterN-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionatemethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(2-morpholinoethoxy)phenylalaninamideN-(2-methoxyethyl)-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-2-amino3-methoxypropionamideN-[N-(3,5-difluorophenylacetyl)-L-alaninylglycine methyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4-pyridyl)propionamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(2-pyridyl)propionamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol4-yl)propionatemethyl ester2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylatemethyl esterN-(3-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(1-naphthyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propionatemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninebenzyl ester N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine3-bromo-propyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-iodopropylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butylesterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N_(ε)-(tert-butoxycarbonyl)-L-lysinemethyl ester methylN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino4-phenylbutanoateN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetamideN-[N-(phenylacetyl)-L-alaninyl]-L-threonine methyl esterN′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN′-[N-(phenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN′-[N-(phenylacetyl)-L-alaninyl)-L-valinamide N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate ethylester N-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-leucinamideN,N-dimethyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamideN-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-phenylalaninamideN-methyl-N′-[N-(phenylacetyl)-L-alaninyl]-L-valinamideN-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino2-(4-methoxyphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetateethyl ester N-[N-(cyclohexylacetyl)-L-alaninyl]-L-phenylalanine methylester N-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxylatemethyl esterN-2-(N,N-dimethylamino)ethyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl esterN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-alanine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]glycine ethyl esterN-hydroxy-N′-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamideN-[N-(isovaleryl)-L-phenylglycinyl]-L-alanine isobutyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-2-amino-3-(3-hydroxyphenyl)propionatemethyl ester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-tyrosine ethylester N-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl esterN-[N-[N-(isovaleryl)-L-valinyl]-L-phenylglycinyl]-L-alanine isobutylester N-[N-(isovaleryl)-L-phenylalaninyl]-L-alanine iso-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester1-[N-(3-nitrophenylacetyl)-L-alaninyl]-indoline-(S)-2-carboxylate ethylester N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-methoxy-N-methyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamideN-iso-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN,N-di-n-propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamideN-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-phenylalaninamnideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-iso-butyl-N′-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamideN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-nitrophenyl)-N′-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamideN-(4-nitrophenyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-benzyl-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(3,5difluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alninyl]-L-alaninamideN-(3-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-benzyl-N′-[N-(3,5-difluorophenylacetyl)L-alaninyl]-L-alaninamideN-(4-nitrobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenywaaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]L-tryptophan methyl esterN-(4-methoxybenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(phenylacetyl)-L-phenylglyciniyl]-L-alanine ethyl esterphenylglycine methyl esterN-[N-(cyclohexylacetyl)-L-phenylglycinyl]L-alanine ethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-henylglycine methyl esterphenylglycine methyl esterN-(2-phenylethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionatemethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamideN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-serine ethyl esterN-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-aianinyl]-L-alaninamideN-[(S)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-aianinyl]-L-alaninamideN-(4-fluorobenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-(4-trifluoromethylbenzyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2cyclohexylacetateethyl esterN-(2-methoxyethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(isovaleryl)-2-amino-2-cyclohexylacetyl]-L-alanine ethyl esterN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-(2-pyridylmethyl)-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(2-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(4-pyridylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)acetateethyl ester N-[N-(3,5difluorophenylacetyl)-L-phenylglycinyl]-L-alanineethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionateethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycineneopentyl esterN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine tert-butylester N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl morpholineN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valine ethyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threonine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methylester4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl]morpholine4- [N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholineN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucine methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucineN-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-threoninyl]-L-valine ethylester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoatemethyl ester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-leucine methylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl esterN-2-methoxyethyl-N′[N-(3,5-difuorophenylacetyl)-L-alaninyl]-L-alaninamideN-2-(N,N-dimethylamino)ethyl-N′-[N-(3,5-difuorophenylacetyl)-L-alaninyl]-L-alaninamideN-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninanide3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methylester N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methylester N-(R)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide1-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidineN-(S)-sec-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl esterN-2-fluoroethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN-[(S)-6-methyl-3-oxohept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramideN-4-nitrobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetatemethyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amnino-2-(benzothiophen-2-yl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetateethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyI)-L-alaninyl]-(S)-2-amino2-(2-thienyl)acetatetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)aceticacidN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(&methoxy-2-naphthyl)acetatemethyl ester N-[N-(35-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl)acetatemethyl ester (3S,4S)-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]4-amino3-hydroxy-5-phenylpentanoatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex4-enoatemethyl ester N-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylglycinetert-butyl esterN-tert-butyl-N′-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(4-phenylphenyl)acetamideN-[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycinetert-Butyl EsterN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butylester N-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycinemethyl ester N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methylester N-[N-(phenylacetyl)-L-alaninyl]-L-alanine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-leucine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-isoleucine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-proline methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-phenylalanine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-N_(ε)-(tert-butoxycarbonyl)-L-lysinemethyl ester N-[N-(phenylacetyl)-L-alaninyl]-glycine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-L-valine methyl esterN-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl esterN-[N-(phenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl esterN-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valineN-[N-(phenylacetyl)-L-alaninyl]-L-N-methylalanine methyl esterN-[N-(isovaleryl)-L-phenylglycinyl=-L-alanine iso-butyl esterN-[N-(isovaleryl)-L-isoleucinyl]-L-alanine iso-butyl esterN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-hydroxyproline ethylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide1-[N-(3,5-difluorophenylacetyl)-L-alaninyl]piperidine-2-carboxylatemethyl ester N-[(S)-3-hydroxy-6-methylhept-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-1-phenyleth-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenyl-α-fluoroacetyl)-L-alaniny]-L-phenylglycinetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycinemethyl esterN-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-2-methoxyethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN-[(S)-α-hydroxy-α-phenyl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-1,2-diphenylethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-hydroxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-hydroxy-α′-(4-hydroxyphenyl)-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-2-pyridylmethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamideN-[e-hydroxy-α′-pyrid-2-yl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-hydroxy-a′-pyrid-4-yl-iso-propyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-hydroxy-4-methylpent-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[α-methoxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-hydroxy-3-methyl-but-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)acetatemethyl esterN-[1-hydroxy-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-methoxy-1-phenyleth-1-yl]-N′-(3,5difluorophenylacetyl)-L-alaninamideN-[(S)-1-methoxy-2-phenyl-prop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)- 1-acetoxyhex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[2-hydroxy-1-(thien-2-yl)ethyl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalaninetert-butyl esterN-[N-(3,5-difuorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(cyclopropaneacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(cyclopentaneacetyl)-L-phenylglycinyl]-L-phenylglycinolN-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamideN-[N-(2-thienylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(n-caprotyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine methylester N-[N-(3,5difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycinemethyl esterN-[N-(3,5difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl esterN-[N-(cyclopropylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butylester N-[N-(cyclopentylacetyl)-L-phenylglycinyl]-L-phenylglycinetert-butyl ester N-[N-(tert-butylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alainyl]-D-(thien-2-yl)glycinanideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothien-2-yl)glycinamideN-Cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamideN-(S)-(−)-α-methylbenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphenyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)phenylglycinamideN-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamideN-cyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-(phenyl)phenylglycinamideN-[N-(3,5-difluorophenyl-α-hydroxyacetyl)-L-alaninyl]-L-phenylglycinetert-butyl esterN-tert-butyl-N′-[N-(3,5-difluorophenyl-α,α-difluoroacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-butylesterN-[(S)-1-oxo-1-phenylprop-2-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycinetert-butyl ester[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-butoxycarbonyl(hydroxyl amine) esterN-neopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidineN-iso-butyl-N′-[N-(3,5difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-cyclopropanemethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl-]D,L-phenylglycinamideN-methoxy-N-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2-methylprop-2-enyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-(pyrid-3-yl)mnethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-(pyrid-4-yl)methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-furfuryl-N′-N′-[N-(3,5-difuorophenylacetyl)-L-alaniny]-D,L-phenylglycinamideN-cyclopentyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-1-benzylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN,N-dimethyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2,2,6,6-tetramethylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-2-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-4-methylcyclohexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-1-ethoxycarbonylpiperidin-4-yl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-methyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-tert-butoxy-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycineN-tert-butyl(hydroxylamine) esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazideN-(1-ethoxyethen-1-yl)-[N′-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinehydrazide N-[N-(phenylacetyl)-L-alaninyl]-L-phenylglycine tert-butylesterN-4-(phenyl)butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-3-(4-iodophenoxy)propyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-6-(amino)hexyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamideHydrochlorideN-1-(phthalimido)pent-2-yl-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycinemethyl ester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucineN-[N-(cyclopentaneacetyl)-L-alaninyl]-L-phenylglycine tert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycineiso-propyl ester N-(isopropyl)N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[N-(cyclopentylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl esterN-[N-(cyclopropylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl esterN-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-phenylglycine isbutylester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methylester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-(3-α-phenyl)prolinemethyl ester N-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-L-azetidinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl-]2-amino-3-(5-chlorobenzothiophen-2-yl)acetatemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino3-(thiazolyl)propionate tert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamidetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamideN-[N-(3,⁴-dichlorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-bromophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(4-methylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-trifluoromethylphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3-methoxyphenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(2-chlorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(1-naphthylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(²-naphthylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(phenylacetyl)-L-alaninyl]-D-phenylglycinamideN-[N-(3,5-fluorhenylacetyi)-L-alaninyl]-D-phenylglycineN-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino2-(2-furanyl)acetamideN′-[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamideN′-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfonamideN″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN″-methyl-N″-phenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamideN″-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamideN″-methyl-N″-benzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamideN″-4-fluorobenzyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycineneopentyl ester N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine methylester N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycinetert-butyl esterN-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycinemethyl esterN-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methylester N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methylesterN″-4-methylphenyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN″-tetrahydrofurfuryl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamideN′-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamideN-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamideN-[(R)-α-methylbenzyl]-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-pentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN-[1-phenyl-2-oxo-butan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-α-hydroxyphenylalaninemethyl esterN″-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-[(S)-1-phenyl-2-oxo2-phenyl-ethan-1-yl]-N′-(3,5-difluorophenyl-acetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L4-fluorophenylglycinetert-butyl esterN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycinetert-butyl ester[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(2,3-benzo[b]proline) methylesterN″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylphenylglycinamideN″-tert-butyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L4-(phenylacetenyl)phenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamideN-[1,3-diphenyl-2-oxo-propan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-hexan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN″-n-hexyl-6-biotinamidyl-N′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamideN′-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionineN′-[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methylester N″-tert-butylN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamideN′-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methylesterN-[(S)-1-phenyl-2-oxo3-phenylpropan-1-yl]-N′-(3,5-difluorophenylacetyl)-L-alaninamideN′-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycineN′-[N-(3,5difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycinetert-butyl esterN′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycineN′-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycinetert-butyl esterN-[2-hydroxy-1-(S)phenyleth-1-yl]-N′-[(3,5difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamideN-[2-hydroxyeth-1-yl]-N′-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamideN-′-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycinetert-butyl ester[N-(2,5-dichlorophenoxyacetyl)-L-alaninyl-L-phenylglycine methyl ester[N-(3,5-difluorophenoxyacetyl)-L-alaninyl]-L-phenylglycine methyl ester[N-(3,4-dichlorothiophenoxyacetyl)-L-alaninyl]-L-phenylglycine methylester [N-(3-aminoproprionyl)-L-alaninyl]-L-phenylglycine tert-butylester; and[N-(3-tert-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycinetert-butyl ester.